Matthew R.G. Taylor, MD, PhD

While much has been said about how advances in genetic testing technology have improved the diagnosis of Mendelian genetic disease, this so-called "next generation" genetic technology is finding other niches. The ability of next-generation sequencing methods to quantitatively measure all genomic material in a laboratory specimen has led several groups to search for modest genetic signals representing a minority of the overall genetic material within a sample.

One area garnering increasing attention is the application of high-throughput sequencing to measure the presence of low levels of tumor DNA in blood as a marker of early metastatic disease.

Except in the most advanced and widespread terminal cancer cases, human cancer cells represent a relatively small population of undesirable cells among a far larger number of normal, ostensibly healthy cells in a patient. Like an unwelcome guest in an otherwise harmonious community, a cancer and its subsequent metastatic offshoots are initially very difficult to detect, because of their being composed of small numbers of cells and being too small in volume to produce a visibly detectable tumor.

Presumably, cancer cells detected at this subclinical stage could be more amenable to treatment and even cure if they could be reliably detected and measured. A large field of biomarker driven research has arisen directly to develop novel strategies for locating proverbial "needle in a haystack" markers of early cancer or early metastatic disease.

Since the discovery of small amounts of circulating cell-free tumor DNA in cancer patients in the past decade, the race has been on to exploit circulating tumor DNA as a possible biomarker of recurrent disease.

A recent paper published in the New England Journal of Medicine illustrates how quickly this approach is becoming applicable in the clinical setting (2013;368:1199-209).

The study focused on women with metastatic breast cancer undergoing systemic chemotherapy. The researchers investigated whether circulating tumor DNA in the women was detectable and had promise as a marker of disease progression and response to therapy. In parallel, the cancer marker CA 15-3 and an assay to capture and count circulating tumor cells were also studied.

Over the course of the 1-year study, 52 women were recruited, 30 of whom had DNA alterations that were believed to be detectable in blood by a genetic approach. These mutations represented DNA differences in the tumor cells from the patient, effectively providing a calling card for each cancer. At approximately 3-week intervals, blood was collected and subjected to either a targeted tumor-gene analysis or broad whole-genome analysis searching for the presence of the tumor-cell DNA calling-card signatures from cell-free DNA.

In the case of the targeted approach, two genes commonly mutated in breast cancer (PIK3CA and TP53) were selectively analyzed and found to contain mutations in 25 of the 52 patients.

The investigators performed whole-genome analysis in 9 of the 52 patients, comparing tumor tissue to matched normal tissue from each patient. This yielded eight patients in whom significant genome differences were found between tumor and normal tissue – and five of those eight patients had no PIK3CA or TP53 mutation.

Thus, 30 of the 52 women had identified genomic alterations. Using either the targeted or whole-genome approach across the 141 serial samples in these 30 patients with mutations, cell-free DNA was detected in 29 (97%) of the women and 115 (82%) of the samples. The one patient with no detectable tumor DNA had a low tumor burden and did not progress during the study.

The levels of cell-free tumor DNA correlated well with the response to therapy during the study, and the number of copies of the tumor DNA found in blood correlated with patient prognosis.

Overall, the study is principally remarkable for its value as a proof-of-concept study. It showed that tumor DNA was detectable in about 60% of the patients with metastatic disease, and that tumor DNA metrics correlated with clinical progression measures.

The two-gene targeted approach was probably more cost effective. However, over the long haul, the need to develop custom PIK3CA and TP53 mutation assays for each patient – and the soon-to-arrive ability of whole-genome approaches to detect PIK3CA and TP53 and many additional mutations at a lower cost – will likely make the genomic approach more favorable.

New algorithms also will need to be developed to improve the sensitivity of variant detection in the remaining 40% of cases that did not have a genetic tumor signature in this study.

In spite of the early stage conclusions from this study, it is tempting to imagine how cell-free tumor DNA analysis might have a role in the initial staging of a cancer diagnosis and as a measure of patient response to therapy.

Possibly, this approach could be used in primary screening for malignancies in patients at risk for cancers (smokers, inflammatory bowel disease, hepatitis B, etc.) or even in the general population. Could even mammography one day be replaced by a cell-free DNA approach?

Cell-free DNA analysis already has an emerging role in detecting fetal cell-free DNA in early-stage pregnancy to identify cases of Down syndrome and other karyotype anomalies before the typical timing of more traditional serum and imaging testing. Similar advances in the microbiome field – measuring entire populations of bacteria and viruses in body fluids and tissues, rather than merely what major specie(s) will grow in culture medium – show another area where high-throughput DNA/RNA analysis has a foothold.

Internists and other physicians alike will need to continue to learn more about these emerging approaches, approaches that seem destined to provide far more quantitative insight into disease biology than previously possible.

Dr. Taylor is with the department of internal medicine and is director of adult clinical genetics at the University of Colorado at Denver, Aurora. He reported having no conflicts of interest.

While much has been said about how advances in genetic testing technology have improved the diagnosis of Mendelian genetic disease, this so-called "next generation" genetic technology is finding other niches. The ability of next-generation sequencing methods to quantitatively measure all genomic material in a laboratory specimen has led several groups to search for modest genetic signals representing a minority of the overall genetic material within a sample.

One area garnering increasing attention is the application of high-throughput sequencing to measure the presence of low levels of tumor DNA in blood as a marker of early metastatic disease.

Except in the most advanced and widespread terminal cancer cases, human cancer cells represent a relatively small population of undesirable cells among a far larger number of normal, ostensibly healthy cells in a patient. Like an unwelcome guest in an otherwise harmonious community, a cancer and its subsequent metastatic offshoots are initially very difficult to detect, because of their being composed of small numbers of cells and being too small in volume to produce a visibly detectable tumor.

Presumably, cancer cells detected at this subclinical stage could be more amenable to treatment and even cure if they could be reliably detected and measured. A large field of biomarker driven research has arisen directly to develop novel strategies for locating proverbial "needle in a haystack" markers of early cancer or early metastatic disease.

Since the discovery of small amounts of circulating cell-free tumor DNA in cancer patients in the past decade, the race has been on to exploit circulating tumor DNA as a possible biomarker of recurrent disease.

A recent paper published in the New England Journal of Medicine illustrates how quickly this approach is becoming applicable in the clinical setting (2013;368:1199-209).

The study focused on women with metastatic breast cancer undergoing systemic chemotherapy. The researchers investigated whether circulating tumor DNA in the women was detectable and had promise as a marker of disease progression and response to therapy. In parallel, the cancer marker CA 15-3 and an assay to capture and count circulating tumor cells were also studied.

Over the course of the 1-year study, 52 women were recruited, 30 of whom had DNA alterations that were believed to be detectable in blood by a genetic approach. These mutations represented DNA differences in the tumor cells from the patient, effectively providing a calling card for each cancer. At approximately 3-week intervals, blood was collected and subjected to either a targeted tumor-gene analysis or broad whole-genome analysis searching for the presence of the tumor-cell DNA calling-card signatures from cell-free DNA.

In the case of the targeted approach, two genes commonly mutated in breast cancer (PIK3CA and TP53) were selectively analyzed and found to contain mutations in 25 of the 52 patients.

The investigators performed whole-genome analysis in 9 of the 52 patients, comparing tumor tissue to matched normal tissue from each patient. This yielded eight patients in whom significant genome differences were found between tumor and normal tissue – and five of those eight patients had no PIK3CA or TP53 mutation.

Thus, 30 of the 52 women had identified genomic alterations. Using either the targeted or whole-genome approach across the 141 serial samples in these 30 patients with mutations, cell-free DNA was detected in 29 (97%) of the women and 115 (82%) of the samples. The one patient with no detectable tumor DNA had a low tumor burden and did not progress during the study.

The levels of cell-free tumor DNA correlated well with the response to therapy during the study, and the number of copies of the tumor DNA found in blood correlated with patient prognosis.

Overall, the study is principally remarkable for its value as a proof-of-concept study. It showed that tumor DNA was detectable in about 60% of the patients with metastatic disease, and that tumor DNA metrics correlated with clinical progression measures.

The two-gene targeted approach was probably more cost effective. However, over the long haul, the need to develop custom PIK3CA and TP53 mutation assays for each patient – and the soon-to-arrive ability of whole-genome approaches to detect PIK3CA and TP53 and many additional mutations at a lower cost – will likely make the genomic approach more favorable.

New algorithms also will need to be developed to improve the sensitivity of variant detection in the remaining 40% of cases that did not have a genetic tumor signature in this study.

In spite of the early stage conclusions from this study, it is tempting to imagine how cell-free tumor DNA analysis might have a role in the initial staging of a cancer diagnosis and as a measure of patient response to therapy.

Possibly, this approach could be used in primary screening for malignancies in patients at risk for cancers (smokers, inflammatory bowel disease, hepatitis B, etc.) or even in the general population. Could even mammography one day be replaced by a cell-free DNA approach?

Cell-free DNA analysis already has an emerging role in detecting fetal cell-free DNA in early-stage pregnancy to identify cases of Down syndrome and other karyotype anomalies before the typical timing of more traditional serum and imaging testing. Similar advances in the microbiome field – measuring entire populations of bacteria and viruses in body fluids and tissues, rather than merely what major specie(s) will grow in culture medium – show another area where high-throughput DNA/RNA analysis has a foothold.

Internists and other physicians alike will need to continue to learn more about these emerging approaches, approaches that seem destined to provide far more quantitative insight into disease biology than previously possible.

Dr. Taylor is with the department of internal medicine and is director of adult clinical genetics at the University of Colorado at Denver, Aurora. He reported having no conflicts of interest.

While much has been said about how advances in genetic testing technology have improved the diagnosis of Mendelian genetic disease, this so-called "next generation" genetic technology is finding other niches. The ability of next-generation sequencing methods to quantitatively measure all genomic material in a laboratory specimen has led several groups to search for modest genetic signals representing a minority of the overall genetic material within a sample.

One area garnering increasing attention is the application of high-throughput sequencing to measure the presence of low levels of tumor DNA in blood as a marker of early metastatic disease.

Except in the most advanced and widespread terminal cancer cases, human cancer cells represent a relatively small population of undesirable cells among a far larger number of normal, ostensibly healthy cells in a patient. Like an unwelcome guest in an otherwise harmonious community, a cancer and its subsequent metastatic offshoots are initially very difficult to detect, because of their being composed of small numbers of cells and being too small in volume to produce a visibly detectable tumor.

Presumably, cancer cells detected at this subclinical stage could be more amenable to treatment and even cure if they could be reliably detected and measured. A large field of biomarker driven research has arisen directly to develop novel strategies for locating proverbial "needle in a haystack" markers of early cancer or early metastatic disease.

Since the discovery of small amounts of circulating cell-free tumor DNA in cancer patients in the past decade, the race has been on to exploit circulating tumor DNA as a possible biomarker of recurrent disease.

A recent paper published in the New England Journal of Medicine illustrates how quickly this approach is becoming applicable in the clinical setting (2013;368:1199-209).

The study focused on women with metastatic breast cancer undergoing systemic chemotherapy. The researchers investigated whether circulating tumor DNA in the women was detectable and had promise as a marker of disease progression and response to therapy. In parallel, the cancer marker CA 15-3 and an assay to capture and count circulating tumor cells were also studied.

Over the course of the 1-year study, 52 women were recruited, 30 of whom had DNA alterations that were believed to be detectable in blood by a genetic approach. These mutations represented DNA differences in the tumor cells from the patient, effectively providing a calling card for each cancer. At approximately 3-week intervals, blood was collected and subjected to either a targeted tumor-gene analysis or broad whole-genome analysis searching for the presence of the tumor-cell DNA calling-card signatures from cell-free DNA.

In the case of the targeted approach, two genes commonly mutated in breast cancer (PIK3CA and TP53) were selectively analyzed and found to contain mutations in 25 of the 52 patients.

The investigators performed whole-genome analysis in 9 of the 52 patients, comparing tumor tissue to matched normal tissue from each patient. This yielded eight patients in whom significant genome differences were found between tumor and normal tissue – and five of those eight patients had no PIK3CA or TP53 mutation.

Thus, 30 of the 52 women had identified genomic alterations. Using either the targeted or whole-genome approach across the 141 serial samples in these 30 patients with mutations, cell-free DNA was detected in 29 (97%) of the women and 115 (82%) of the samples. The one patient with no detectable tumor DNA had a low tumor burden and did not progress during the study.

The levels of cell-free tumor DNA correlated well with the response to therapy during the study, and the number of copies of the tumor DNA found in blood correlated with patient prognosis.

Overall, the study is principally remarkable for its value as a proof-of-concept study. It showed that tumor DNA was detectable in about 60% of the patients with metastatic disease, and that tumor DNA metrics correlated with clinical progression measures.

The two-gene targeted approach was probably more cost effective. However, over the long haul, the need to develop custom PIK3CA and TP53 mutation assays for each patient – and the soon-to-arrive ability of whole-genome approaches to detect PIK3CA and TP53 and many additional mutations at a lower cost – will likely make the genomic approach more favorable.

New algorithms also will need to be developed to improve the sensitivity of variant detection in the remaining 40% of cases that did not have a genetic tumor signature in this study.

In spite of the early stage conclusions from this study, it is tempting to imagine how cell-free tumor DNA analysis might have a role in the initial staging of a cancer diagnosis and as a measure of patient response to therapy.

Possibly, this approach could be used in primary screening for malignancies in patients at risk for cancers (smokers, inflammatory bowel disease, hepatitis B, etc.) or even in the general population. Could even mammography one day be replaced by a cell-free DNA approach?

Cell-free DNA analysis already has an emerging role in detecting fetal cell-free DNA in early-stage pregnancy to identify cases of Down syndrome and other karyotype anomalies before the typical timing of more traditional serum and imaging testing. Similar advances in the microbiome field – measuring entire populations of bacteria and viruses in body fluids and tissues, rather than merely what major specie(s) will grow in culture medium – show another area where high-throughput DNA/RNA analysis has a foothold.

Internists and other physicians alike will need to continue to learn more about these emerging approaches, approaches that seem destined to provide far more quantitative insight into disease biology than previously possible.

Dr. Taylor is with the department of internal medicine and is director of adult clinical genetics at the University of Colorado at Denver, Aurora. He reported having no conflicts of interest.

Most of us think of genetic mutations as damaging DNA changes that either directly cause a disease or increase one’s risk of developing an illness later in life.

Because mutations occur in a mostly nonrandom fashion, the majority of mutations are expected to be more likely deleterious or neutral rather than beneficial. An analogy is that if a person who had never seen or heard of a car were to open a car’s hood and rearrange or remove one piece of the engine, the result would mostly likely be neutral or damaging to the car’s function.

In spite of the expected negative or neutral consequences of most genetic changes, some mutations with positive effects do occur and remain a source of great interest to researchers. A recent example of one such mutation was reported last month by Thorlakur Jonsson, Ph.D., of deCODE genetics in Reykjavik, Iceland, and colleagues, who studied Alzheimer’s disease and adult-onset cognitive decline in Icelanders (Nature 2012;488:96-9).

Dementia is a significant medicocognitive condition of later life, affecting over 24 million persons worldwide, with the vast majority of these cases being caused by Alzheimer’s disease. Estimates rise steadily for the continued increased prevalence of dementia as populations age, from approximately 5% at age 60 years to greater than 25% by age 90. Mild cognitive impairment, which often precedes a diagnosis of dementia, is estimated to affect 10%-20% of those older than 65 years, and will likely also increase in prevalence as aging trends continue. It is estimated that only 1% of persons experience no cognitive decline at all, even in old age.

The pathological diagnosis of Alzheimer’s disease requires documented findings of amyloid plaques and neurofibrillary tangles in the brain either by biopsy or postmortem examination – procedures that are performed in only a minority of patients. Current disease models implicate the accumulation of amyloid-beta as being involved in directly causing the disease, although some have argued that amyloid buildup could be a marker of disease, rather than be directly involved in disease generation.

Dr. Jonsson and colleagues studied the coding portions of the genome in 1,795 Icelanders, and then looked for genetic mutations that affected the risk of both Alzheimer’s disease and cognitive decline. The amyloid-beta precursor protein (APP) had previously been linked to early-onset, genetic forms of Alzheimer’s disease, so the team scanned the APP gene for novel mutations that had an impact on the risk of cognitive function.

To increase the power of their study, the group used computer modeling to impute (that is, predict) the genetic status of biological relatives for whom cognitive status was known, but who had not actually undergone any genetic testing. By using these inferred genetic results, the investigators were able to study their questions in nearly 300,000 subjects. This gave them enough statistical power to compare the genetic status of persons with Alzheimer’s disease vs. other persons who have lived to at least age 85 years without a diagnosis of Alzheimer’s disease.

They identified a mutation at amino-acid position 673 in the APP protein where the normal alanine residue had been replaced by a threonine (A673T). This A673T mutation was found in only 0.5% of Icelanders, but was associated with a 5.3 odds ratio for protection against a diagnosis of Alzheimer’s disease. Interestingly, another genetic mutation at the same amino acid position (A573V) had been previously linked to Alzheimer’s disease, suggesting that this was an important position in the APP protein. The A673T mutation also appeared to be predictive of having a normal score on a cognitive performance scale (OR, 7.5), and carriers of A673T had a 50% greater chance of living to at least age 85 years.

By comparing the function of the A673T mutation in a biochemical assay, the authors also showed reduced cleavage of the APP protein, compared with the wild-type mutation. These data support the notion that the breakdown rates of the APP protein are indeed relevant to the pathogenesis of Alzheimer’s disease, as opposed to their having a bystander role. As an extension of this notion, drugs that are designed to reduce APP cleavage rates could have a protective effect against Alzheimer’s disease and cognitive decline in general.

As with many studies, this work represents another modest step along the road to understanding and reducing the burden of a human disease. Some commercial genetic testing companies are likely to quickly adopt and market the A673T mutation as an "Alzheimer‘s protection" marker. The general rarity of this mutation should give informed consumers pause about leaping to the conclusion that such a test is a good value for the money. However, the data are sure to fuel interest from pharmaceutical companies that hope to develop an Alzheimer’s disease treatment that would hold more promise than those currently available.

On a more global level, the discovery of a rare variant with a modest risk effect has significance for geneticists searching for the "missing heritability," a vexing problem that speaks to the fact that for many diseases, common genetic variation does not explain as much of the genetic basis of disease as had been hoped. Using these genome-level strategies to discover other rare variants holds new promise in filling these gaps in our understanding.

Dr. Taylor is associate professor in the department of internal medicine and director of adult clinical genetics at the University of Colorado at Denver, Aurora. He reported having no conflicts of interest.

Most of us think of genetic mutations as damaging DNA changes that either directly cause a disease or increase one’s risk of developing an illness later in life.

Because mutations occur in a mostly nonrandom fashion, the majority of mutations are expected to be more likely deleterious or neutral rather than beneficial. An analogy is that if a person who had never seen or heard of a car were to open a car’s hood and rearrange or remove one piece of the engine, the result would mostly likely be neutral or damaging to the car’s function.

In spite of the expected negative or neutral consequences of most genetic changes, some mutations with positive effects do occur and remain a source of great interest to researchers. A recent example of one such mutation was reported last month by Thorlakur Jonsson, Ph.D., of deCODE genetics in Reykjavik, Iceland, and colleagues, who studied Alzheimer’s disease and adult-onset cognitive decline in Icelanders (Nature 2012;488:96-9).

Dementia is a significant medicocognitive condition of later life, affecting over 24 million persons worldwide, with the vast majority of these cases being caused by Alzheimer’s disease. Estimates rise steadily for the continued increased prevalence of dementia as populations age, from approximately 5% at age 60 years to greater than 25% by age 90. Mild cognitive impairment, which often precedes a diagnosis of dementia, is estimated to affect 10%-20% of those older than 65 years, and will likely also increase in prevalence as aging trends continue. It is estimated that only 1% of persons experience no cognitive decline at all, even in old age.

The pathological diagnosis of Alzheimer’s disease requires documented findings of amyloid plaques and neurofibrillary tangles in the brain either by biopsy or postmortem examination – procedures that are performed in only a minority of patients. Current disease models implicate the accumulation of amyloid-beta as being involved in directly causing the disease, although some have argued that amyloid buildup could be a marker of disease, rather than be directly involved in disease generation.

Dr. Jonsson and colleagues studied the coding portions of the genome in 1,795 Icelanders, and then looked for genetic mutations that affected the risk of both Alzheimer’s disease and cognitive decline. The amyloid-beta precursor protein (APP) had previously been linked to early-onset, genetic forms of Alzheimer’s disease, so the team scanned the APP gene for novel mutations that had an impact on the risk of cognitive function.

To increase the power of their study, the group used computer modeling to impute (that is, predict) the genetic status of biological relatives for whom cognitive status was known, but who had not actually undergone any genetic testing. By using these inferred genetic results, the investigators were able to study their questions in nearly 300,000 subjects. This gave them enough statistical power to compare the genetic status of persons with Alzheimer’s disease vs. other persons who have lived to at least age 85 years without a diagnosis of Alzheimer’s disease.

They identified a mutation at amino-acid position 673 in the APP protein where the normal alanine residue had been replaced by a threonine (A673T). This A673T mutation was found in only 0.5% of Icelanders, but was associated with a 5.3 odds ratio for protection against a diagnosis of Alzheimer’s disease. Interestingly, another genetic mutation at the same amino acid position (A573V) had been previously linked to Alzheimer’s disease, suggesting that this was an important position in the APP protein. The A673T mutation also appeared to be predictive of having a normal score on a cognitive performance scale (OR, 7.5), and carriers of A673T had a 50% greater chance of living to at least age 85 years.

By comparing the function of the A673T mutation in a biochemical assay, the authors also showed reduced cleavage of the APP protein, compared with the wild-type mutation. These data support the notion that the breakdown rates of the APP protein are indeed relevant to the pathogenesis of Alzheimer’s disease, as opposed to their having a bystander role. As an extension of this notion, drugs that are designed to reduce APP cleavage rates could have a protective effect against Alzheimer’s disease and cognitive decline in general.

As with many studies, this work represents another modest step along the road to understanding and reducing the burden of a human disease. Some commercial genetic testing companies are likely to quickly adopt and market the A673T mutation as an "Alzheimer‘s protection" marker. The general rarity of this mutation should give informed consumers pause about leaping to the conclusion that such a test is a good value for the money. However, the data are sure to fuel interest from pharmaceutical companies that hope to develop an Alzheimer’s disease treatment that would hold more promise than those currently available.

On a more global level, the discovery of a rare variant with a modest risk effect has significance for geneticists searching for the "missing heritability," a vexing problem that speaks to the fact that for many diseases, common genetic variation does not explain as much of the genetic basis of disease as had been hoped. Using these genome-level strategies to discover other rare variants holds new promise in filling these gaps in our understanding.

Dr. Taylor is associate professor in the department of internal medicine and director of adult clinical genetics at the University of Colorado at Denver, Aurora. He reported having no conflicts of interest.

Most of us think of genetic mutations as damaging DNA changes that either directly cause a disease or increase one’s risk of developing an illness later in life.

Because mutations occur in a mostly nonrandom fashion, the majority of mutations are expected to be more likely deleterious or neutral rather than beneficial. An analogy is that if a person who had never seen or heard of a car were to open a car’s hood and rearrange or remove one piece of the engine, the result would mostly likely be neutral or damaging to the car’s function.

In spite of the expected negative or neutral consequences of most genetic changes, some mutations with positive effects do occur and remain a source of great interest to researchers. A recent example of one such mutation was reported last month by Thorlakur Jonsson, Ph.D., of deCODE genetics in Reykjavik, Iceland, and colleagues, who studied Alzheimer’s disease and adult-onset cognitive decline in Icelanders (Nature 2012;488:96-9).

Dementia is a significant medicocognitive condition of later life, affecting over 24 million persons worldwide, with the vast majority of these cases being caused by Alzheimer’s disease. Estimates rise steadily for the continued increased prevalence of dementia as populations age, from approximately 5% at age 60 years to greater than 25% by age 90. Mild cognitive impairment, which often precedes a diagnosis of dementia, is estimated to affect 10%-20% of those older than 65 years, and will likely also increase in prevalence as aging trends continue. It is estimated that only 1% of persons experience no cognitive decline at all, even in old age.

The pathological diagnosis of Alzheimer’s disease requires documented findings of amyloid plaques and neurofibrillary tangles in the brain either by biopsy or postmortem examination – procedures that are performed in only a minority of patients. Current disease models implicate the accumulation of amyloid-beta as being involved in directly causing the disease, although some have argued that amyloid buildup could be a marker of disease, rather than be directly involved in disease generation.

Dr. Jonsson and colleagues studied the coding portions of the genome in 1,795 Icelanders, and then looked for genetic mutations that affected the risk of both Alzheimer’s disease and cognitive decline. The amyloid-beta precursor protein (APP) had previously been linked to early-onset, genetic forms of Alzheimer’s disease, so the team scanned the APP gene for novel mutations that had an impact on the risk of cognitive function.

To increase the power of their study, the group used computer modeling to impute (that is, predict) the genetic status of biological relatives for whom cognitive status was known, but who had not actually undergone any genetic testing. By using these inferred genetic results, the investigators were able to study their questions in nearly 300,000 subjects. This gave them enough statistical power to compare the genetic status of persons with Alzheimer’s disease vs. other persons who have lived to at least age 85 years without a diagnosis of Alzheimer’s disease.

They identified a mutation at amino-acid position 673 in the APP protein where the normal alanine residue had been replaced by a threonine (A673T). This A673T mutation was found in only 0.5% of Icelanders, but was associated with a 5.3 odds ratio for protection against a diagnosis of Alzheimer’s disease. Interestingly, another genetic mutation at the same amino acid position (A573V) had been previously linked to Alzheimer’s disease, suggesting that this was an important position in the APP protein. The A673T mutation also appeared to be predictive of having a normal score on a cognitive performance scale (OR, 7.5), and carriers of A673T had a 50% greater chance of living to at least age 85 years.

By comparing the function of the A673T mutation in a biochemical assay, the authors also showed reduced cleavage of the APP protein, compared with the wild-type mutation. These data support the notion that the breakdown rates of the APP protein are indeed relevant to the pathogenesis of Alzheimer’s disease, as opposed to their having a bystander role. As an extension of this notion, drugs that are designed to reduce APP cleavage rates could have a protective effect against Alzheimer’s disease and cognitive decline in general.

As with many studies, this work represents another modest step along the road to understanding and reducing the burden of a human disease. Some commercial genetic testing companies are likely to quickly adopt and market the A673T mutation as an "Alzheimer‘s protection" marker. The general rarity of this mutation should give informed consumers pause about leaping to the conclusion that such a test is a good value for the money. However, the data are sure to fuel interest from pharmaceutical companies that hope to develop an Alzheimer’s disease treatment that would hold more promise than those currently available.

On a more global level, the discovery of a rare variant with a modest risk effect has significance for geneticists searching for the "missing heritability," a vexing problem that speaks to the fact that for many diseases, common genetic variation does not explain as much of the genetic basis of disease as had been hoped. Using these genome-level strategies to discover other rare variants holds new promise in filling these gaps in our understanding.

Dr. Taylor is associate professor in the department of internal medicine and director of adult clinical genetics at the University of Colorado at Denver, Aurora. He reported having no conflicts of interest.

When I was in medical school in the early 1990s, the basic model for cancer was that a single cell harboring a mutation, often caused by exposure to tobacco or radiation, was the inciting event leading to malignancy. Over time, this cell divided hundreds of time, developing into a "clonal population" of identically malignant cells able to thwart the body’s immune and cancer surveillance system and resulting eventually in a tumor. Left unchecked, the monoclonal tumor gradually spread around the body, beyond the realm of a surgical cure, leaving toxic chemotherapy as the sole option.

The concept of tumor evolution was mainly framed around tumor growth and perhaps the acquisition of additional mutations that increased tumor aggression. However, even in the multi-step models of tumor progression the implication was that the cancer itself was essentially a monoclonal beast to be removed by the timely surgeon or beaten back by chemotherapy. This model, an oversimplification understandable to medical students, has been questioned in recent years as genetic studies of tumor tissue reveal tumors to be more dynamic and more heterogeneous than originally thought.

Photo credit: Kativ/iStockphoto.com

An elegant genomics study recently published by Dr. Marco Gerlinger of the Cancer Research UK London Research Institute and colleagues further highlights that cancers can be conceptualized as heterogeneous collections of cancer cells that are constantly evolving and possibly even competing in Darwinian fashion for their right to exist and prosper at the expense of the host (N. Engl. J. Med. 2012;366:10:883-92).

Dr. Gerlinger’s group examined primary and metastatic tumor specimens in four patients with advanced renal cancer. Genomic analysis was done at various time points, including prior to the initiation of chemotherapy and at times of cancer progression. The genomic analysis included whole-exome sequencing, or DNA sequencing of all the known human genes (see "Personalized Genome Around the Corner?" Genetics in Your Practice, March 1, 2010, p. 58), allowing the team to look for the signs of tumor evolution as new genetic mutations arose from primary to metastatic disease as well as after exposure to chemotherapy. Furthermore, it was possible to look at different regions of the tumor specimen at the same time point, directly addressing the dated concept of a tumor being a monoclonal tissue.

The results showed heterogeneity in the tumors with respect to time and exposure to chemotherapy. In one patient – from who over a dozen different tumor specimens were analyzed, including nine from different regions of the surgically excised primary tumor – over 125 genetic mutations were identified in the primary analysis. A subset was then validated to confirm the findings of the initial genomic analysis.

Several interesting findings came out of the work. Roughly one-third of the mutations present in all biopsy specimens from the patient fit with the monoclonal model. An additional 45% were shared by some but not all tumor samples, and just over 20% were seemingly unique and present in just a single biopsy. This meant that, overall, most mutations detected were not found in all tumor specimens and that regional differences across the tumor were quite prevalent.

Although not all of these mutations likely contribute to the behavior of the cancer, the data do paint a picture of a tumor that is nonuniform in a genetic sense, with evidence for genetic uniqueness when one drills down to the level of a specific tumor region. There could be unique mutations present in just one or a few cells, although the study did not reach this degree of granularity.

Interestingly, some mutations appeared to arise more than once and, as a given tumor progressed, seemed to increase temporally in the tumor, a form of convergent evolution. This suggests that various natural selection forces, including perhaps exposure to chemotherapy, fueled a Darwinian selection process as the tumors adapted in ways that favored growth and propagation.

The fact that this intra-tumor heterogeneity and "oncogenic Darwinism" occurs in tumors is sobering. It implies that each tumor represents not just a unique substrate for a given patient, but rather a collection of multiple unique communities of cancer cells.

Just as DNA fingerprinting reveals that every individual, save identical twins, is genetically unique, these tumor data show that it may be true that each separate cancer is unique and even that each cancer within an individual is constantly evolving from a genetic standpoint. Some of this variation may explain the limitations of chemotherapies that cannot always eradicate a cancer. Furthermore, the data raise questions about how to design personalized therapies that specifically address the moving target problem of a heterogeneous and dynamically evolving tumor.

As the study investigators point out, however, quantifying and understanding the extent of this variation still represent important steps in better understanding cancer prognosis, as well as the development of new treatment strategies.

Dr. Taylor is associate professor in the department of internal medicine and director of adult clinical genetics at the University of Colorado at Denver. He reports having no conflicts of interest.

When I was in medical school in the early 1990s, the basic model for cancer was that a single cell harboring a mutation, often caused by exposure to tobacco or radiation, was the inciting event leading to malignancy. Over time, this cell divided hundreds of time, developing into a "clonal population" of identically malignant cells able to thwart the body’s immune and cancer surveillance system and resulting eventually in a tumor. Left unchecked, the monoclonal tumor gradually spread around the body, beyond the realm of a surgical cure, leaving toxic chemotherapy as the sole option.

The concept of tumor evolution was mainly framed around tumor growth and perhaps the acquisition of additional mutations that increased tumor aggression. However, even in the multi-step models of tumor progression the implication was that the cancer itself was essentially a monoclonal beast to be removed by the timely surgeon or beaten back by chemotherapy. This model, an oversimplification understandable to medical students, has been questioned in recent years as genetic studies of tumor tissue reveal tumors to be more dynamic and more heterogeneous than originally thought.

Photo credit: Kativ/iStockphoto.com

An elegant genomics study recently published by Dr. Marco Gerlinger of the Cancer Research UK London Research Institute and colleagues further highlights that cancers can be conceptualized as heterogeneous collections of cancer cells that are constantly evolving and possibly even competing in Darwinian fashion for their right to exist and prosper at the expense of the host (N. Engl. J. Med. 2012;366:10:883-92).

Dr. Gerlinger’s group examined primary and metastatic tumor specimens in four patients with advanced renal cancer. Genomic analysis was done at various time points, including prior to the initiation of chemotherapy and at times of cancer progression. The genomic analysis included whole-exome sequencing, or DNA sequencing of all the known human genes (see "Personalized Genome Around the Corner?" Genetics in Your Practice, March 1, 2010, p. 58), allowing the team to look for the signs of tumor evolution as new genetic mutations arose from primary to metastatic disease as well as after exposure to chemotherapy. Furthermore, it was possible to look at different regions of the tumor specimen at the same time point, directly addressing the dated concept of a tumor being a monoclonal tissue.

The results showed heterogeneity in the tumors with respect to time and exposure to chemotherapy. In one patient – from who over a dozen different tumor specimens were analyzed, including nine from different regions of the surgically excised primary tumor – over 125 genetic mutations were identified in the primary analysis. A subset was then validated to confirm the findings of the initial genomic analysis.

Several interesting findings came out of the work. Roughly one-third of the mutations present in all biopsy specimens from the patient fit with the monoclonal model. An additional 45% were shared by some but not all tumor samples, and just over 20% were seemingly unique and present in just a single biopsy. This meant that, overall, most mutations detected were not found in all tumor specimens and that regional differences across the tumor were quite prevalent.

Although not all of these mutations likely contribute to the behavior of the cancer, the data do paint a picture of a tumor that is nonuniform in a genetic sense, with evidence for genetic uniqueness when one drills down to the level of a specific tumor region. There could be unique mutations present in just one or a few cells, although the study did not reach this degree of granularity.

Interestingly, some mutations appeared to arise more than once and, as a given tumor progressed, seemed to increase temporally in the tumor, a form of convergent evolution. This suggests that various natural selection forces, including perhaps exposure to chemotherapy, fueled a Darwinian selection process as the tumors adapted in ways that favored growth and propagation.

The fact that this intra-tumor heterogeneity and "oncogenic Darwinism" occurs in tumors is sobering. It implies that each tumor represents not just a unique substrate for a given patient, but rather a collection of multiple unique communities of cancer cells.

Just as DNA fingerprinting reveals that every individual, save identical twins, is genetically unique, these tumor data show that it may be true that each separate cancer is unique and even that each cancer within an individual is constantly evolving from a genetic standpoint. Some of this variation may explain the limitations of chemotherapies that cannot always eradicate a cancer. Furthermore, the data raise questions about how to design personalized therapies that specifically address the moving target problem of a heterogeneous and dynamically evolving tumor.

As the study investigators point out, however, quantifying and understanding the extent of this variation still represent important steps in better understanding cancer prognosis, as well as the development of new treatment strategies.

Dr. Taylor is associate professor in the department of internal medicine and director of adult clinical genetics at the University of Colorado at Denver. He reports having no conflicts of interest.

When I was in medical school in the early 1990s, the basic model for cancer was that a single cell harboring a mutation, often caused by exposure to tobacco or radiation, was the inciting event leading to malignancy. Over time, this cell divided hundreds of time, developing into a "clonal population" of identically malignant cells able to thwart the body’s immune and cancer surveillance system and resulting eventually in a tumor. Left unchecked, the monoclonal tumor gradually spread around the body, beyond the realm of a surgical cure, leaving toxic chemotherapy as the sole option.

The concept of tumor evolution was mainly framed around tumor growth and perhaps the acquisition of additional mutations that increased tumor aggression. However, even in the multi-step models of tumor progression the implication was that the cancer itself was essentially a monoclonal beast to be removed by the timely surgeon or beaten back by chemotherapy. This model, an oversimplification understandable to medical students, has been questioned in recent years as genetic studies of tumor tissue reveal tumors to be more dynamic and more heterogeneous than originally thought.

Photo credit: Kativ/iStockphoto.com

An elegant genomics study recently published by Dr. Marco Gerlinger of the Cancer Research UK London Research Institute and colleagues further highlights that cancers can be conceptualized as heterogeneous collections of cancer cells that are constantly evolving and possibly even competing in Darwinian fashion for their right to exist and prosper at the expense of the host (N. Engl. J. Med. 2012;366:10:883-92).

Dr. Gerlinger’s group examined primary and metastatic tumor specimens in four patients with advanced renal cancer. Genomic analysis was done at various time points, including prior to the initiation of chemotherapy and at times of cancer progression. The genomic analysis included whole-exome sequencing, or DNA sequencing of all the known human genes (see "Personalized Genome Around the Corner?" Genetics in Your Practice, March 1, 2010, p. 58), allowing the team to look for the signs of tumor evolution as new genetic mutations arose from primary to metastatic disease as well as after exposure to chemotherapy. Furthermore, it was possible to look at different regions of the tumor specimen at the same time point, directly addressing the dated concept of a tumor being a monoclonal tissue.

The results showed heterogeneity in the tumors with respect to time and exposure to chemotherapy. In one patient – from who over a dozen different tumor specimens were analyzed, including nine from different regions of the surgically excised primary tumor – over 125 genetic mutations were identified in the primary analysis. A subset was then validated to confirm the findings of the initial genomic analysis.

Several interesting findings came out of the work. Roughly one-third of the mutations present in all biopsy specimens from the patient fit with the monoclonal model. An additional 45% were shared by some but not all tumor samples, and just over 20% were seemingly unique and present in just a single biopsy. This meant that, overall, most mutations detected were not found in all tumor specimens and that regional differences across the tumor were quite prevalent.

Although not all of these mutations likely contribute to the behavior of the cancer, the data do paint a picture of a tumor that is nonuniform in a genetic sense, with evidence for genetic uniqueness when one drills down to the level of a specific tumor region. There could be unique mutations present in just one or a few cells, although the study did not reach this degree of granularity.

Interestingly, some mutations appeared to arise more than once and, as a given tumor progressed, seemed to increase temporally in the tumor, a form of convergent evolution. This suggests that various natural selection forces, including perhaps exposure to chemotherapy, fueled a Darwinian selection process as the tumors adapted in ways that favored growth and propagation.

The fact that this intra-tumor heterogeneity and "oncogenic Darwinism" occurs in tumors is sobering. It implies that each tumor represents not just a unique substrate for a given patient, but rather a collection of multiple unique communities of cancer cells.

Just as DNA fingerprinting reveals that every individual, save identical twins, is genetically unique, these tumor data show that it may be true that each separate cancer is unique and even that each cancer within an individual is constantly evolving from a genetic standpoint. Some of this variation may explain the limitations of chemotherapies that cannot always eradicate a cancer. Furthermore, the data raise questions about how to design personalized therapies that specifically address the moving target problem of a heterogeneous and dynamically evolving tumor.

As the study investigators point out, however, quantifying and understanding the extent of this variation still represent important steps in better understanding cancer prognosis, as well as the development of new treatment strategies.

Dr. Taylor is associate professor in the department of internal medicine and director of adult clinical genetics at the University of Colorado at Denver. He reports having no conflicts of interest.

I’d like to share how a "typical" clinic day goes for the patients that are referred to my adult genetic medicine practice.

Our first patient is our only return visit of the day and is a 54-year-old man with longstanding intellectual disability of unknown cause. Intellectual disabilities affect 1%-3% of persons and 10% of all families and represent a major public health problem. A significant proportion of cases are presumed to be genetic in etiology, although until relatively recently only a few (roughly 5%) could be diagnosed. Although children with intellectual problems are often evaluated by a comprehensive battery of testing, many adults are not evaluated, or were evaluated in the distant past.

A recent study (Genet. Med. 2010;12:32-8) in adults with unexplained intellectual disabilities found genetic diagnoses in more than 20% of patients and, while curative treatments are typically not possible, the value of a specific diagnosis to the patient’s family and the potential to access additional medical and social services with a confirmed diagnosis often make these investigations worthwhile. The recent development of X-linked "mental retardation" genetic panels that target men with intellectual disabilities will likely increase the diagnostic yield in this area.

Our second patient is a healthy 30-year-old man whose nephew was recently diagnosed with two genetic conditions: DiGeorge syndrome and I-cell disease. The patient and his wife, both present, want to know how this might affect their future children. We spend the first portion of the visit confirming the genetic and laboratory data surrounding the nephew’s unfortunate diagnoses. DiGeorge syndrome, which is caused by loss of genetic material from chromosome 22, is relatively common (1:4,000 infants), and frequently is identified because of cardiac defects, facial dysmorphisms, and learning difficulties. Milder cases might be missed in childhood and can present in adults as hypocalcemia, learning problems, and even schizophrenia. Only 10% of cases are inherited and our medical evaluation and physical exam did not turn up anything suspicious. We reassure the patient that his future children are at low risk for DiGeorge syndrome. I-cell disease, far less common (1:100,000), is unrelated to the DiGeorge diagnosis, but is uniformly fatal. We provide separate counseling for the I-cell risk and arrange for genetic testing to see if our patient is a carrier of an I-cell defect. If he is, his wife will then undergo carrier testing.

Our next patient is a 40-year-old woman with a history of joint hypermobility, chronic joint dislocations, easy bruising, and stretchy skin. Formerly very physically active, she had some pelvic symphysis separation during her last pregnancy and is now unable to work because of chronic pain. This constellation of symptoms represents one of the more-common referrals to adult medical geneticists. Our clinical evaluation confirms that she has a hypermobility syndrome, and we provide recommendations on how to best manage her pain and on a physical therapy regimen designed to improve her muscle tone and reduce the chance of future injuries.

Just before lunch, we have a heartbreaking visit with a 24-year-old woman who, accompanied by her partner and their young daughter, learns of her positive results for Huntington’s disease. At age 24 years, she has no overt symptoms, but the implications of the results are not lost on her as she cared for her grandparent who died from the disease. Furthermore, a psychiatric disorder in her estranged mother is now acknowledged as probable Huntington’s. The patient reveals to us that she is again pregnant and we have a long discussion about the potential risks to this pregnancy and what options she has to address this risk.

The afternoon begins with a full room; a 27-year-old man with Phelan-McDermid syndrome brought in by his parents and two caregivers. Phelan-McDermid syndrome represents one of a growing class of genetic diagnoses that have been recognized and defined only in the past 5-10 years. Involving a slightly different region of chromosome 22 than DiGeorge syndrome, Phelan-McDermid syndrome features cognitive problems including absent speech in many cases. As the diagnosis is unfamiliar to most internists, the family asks for our help in bridging this knowledge gap by serving as a resource to the internist who will be coordinating the primary care for this young man. Since patients with Phelan-McDermid syndrome are generally medically healthy we broach the subject of what plans are in place for the likely possibility that he will outlive his parents.

As the day winds down, we see two cases in which management implications are at the forefront of the discussions. First a 40-year-old man with a lifelong diagnosis of Alport syndrome comes to see us because he needs assistance finding a suitable kidney donor. He had his first transplant more than a decade ago and is again requiring dialysis. His antibody status precludes most unrelated donors and the prime focus is on his sister who has a 50% chance of being an Alport carrier, which would render her unsuitable as a donor. Molecular genetic testing for X-linked Alport is now available in the United States and we make arrangements to use this to find his mutation and then hopefully exclude the mutation in his sister who is a willing donor.

Our final patient is a 29-year-old woman with Fabry’s disease, also X-linked, who is seeking advice on whether she needs to initiate treatment with recombinant enzyme replacement therapy. She has symptoms of pain in her hands and feet and early proteinuria; both findings suggesting microvascular disease caused by her Fabry’s. The mutation in her family also is quite severe, evidenced by others in the family history with severe problems. Based on these findings, we discuss the potential benefits of enzyme replacement therapy and initiate steps to start this therapy.

From these few cases referred to our genetics clinic by internists, it should be clear how far genetics has come, as well as how far it needs to go. Genetic counseling continues to hold value for patients and their families. The advent of hundreds of molecular tests has greatly improved our ability to accurately diagnose genetic conditions and increasingly we turn to our molecular tool boxes to reach a diagnosis, to guide medical management, and even to apply targeted therapy. To be sure, adult genetics clinics remain rare oddities, existing at only at a few academic medical centers. While we are only beginning to apply what we know about genetic medicine, I hope you found this brief glimpse at a "typical" day promising.

Dr. Taylor is associate professor in the department of internal medicine and director of adult clinical genetics at the University of Colorado at Denver.

I’d like to share how a "typical" clinic day goes for the patients that are referred to my adult genetic medicine practice.

Our first patient is our only return visit of the day and is a 54-year-old man with longstanding intellectual disability of unknown cause. Intellectual disabilities affect 1%-3% of persons and 10% of all families and represent a major public health problem. A significant proportion of cases are presumed to be genetic in etiology, although until relatively recently only a few (roughly 5%) could be diagnosed. Although children with intellectual problems are often evaluated by a comprehensive battery of testing, many adults are not evaluated, or were evaluated in the distant past.

A recent study (Genet. Med. 2010;12:32-8) in adults with unexplained intellectual disabilities found genetic diagnoses in more than 20% of patients and, while curative treatments are typically not possible, the value of a specific diagnosis to the patient’s family and the potential to access additional medical and social services with a confirmed diagnosis often make these investigations worthwhile. The recent development of X-linked "mental retardation" genetic panels that target men with intellectual disabilities will likely increase the diagnostic yield in this area.

Our second patient is a healthy 30-year-old man whose nephew was recently diagnosed with two genetic conditions: DiGeorge syndrome and I-cell disease. The patient and his wife, both present, want to know how this might affect their future children. We spend the first portion of the visit confirming the genetic and laboratory data surrounding the nephew’s unfortunate diagnoses. DiGeorge syndrome, which is caused by loss of genetic material from chromosome 22, is relatively common (1:4,000 infants), and frequently is identified because of cardiac defects, facial dysmorphisms, and learning difficulties. Milder cases might be missed in childhood and can present in adults as hypocalcemia, learning problems, and even schizophrenia. Only 10% of cases are inherited and our medical evaluation and physical exam did not turn up anything suspicious. We reassure the patient that his future children are at low risk for DiGeorge syndrome. I-cell disease, far less common (1:100,000), is unrelated to the DiGeorge diagnosis, but is uniformly fatal. We provide separate counseling for the I-cell risk and arrange for genetic testing to see if our patient is a carrier of an I-cell defect. If he is, his wife will then undergo carrier testing.

Our next patient is a 40-year-old woman with a history of joint hypermobility, chronic joint dislocations, easy bruising, and stretchy skin. Formerly very physically active, she had some pelvic symphysis separation during her last pregnancy and is now unable to work because of chronic pain. This constellation of symptoms represents one of the more-common referrals to adult medical geneticists. Our clinical evaluation confirms that she has a hypermobility syndrome, and we provide recommendations on how to best manage her pain and on a physical therapy regimen designed to improve her muscle tone and reduce the chance of future injuries.

Just before lunch, we have a heartbreaking visit with a 24-year-old woman who, accompanied by her partner and their young daughter, learns of her positive results for Huntington’s disease. At age 24 years, she has no overt symptoms, but the implications of the results are not lost on her as she cared for her grandparent who died from the disease. Furthermore, a psychiatric disorder in her estranged mother is now acknowledged as probable Huntington’s. The patient reveals to us that she is again pregnant and we have a long discussion about the potential risks to this pregnancy and what options she has to address this risk.

The afternoon begins with a full room; a 27-year-old man with Phelan-McDermid syndrome brought in by his parents and two caregivers. Phelan-McDermid syndrome represents one of a growing class of genetic diagnoses that have been recognized and defined only in the past 5-10 years. Involving a slightly different region of chromosome 22 than DiGeorge syndrome, Phelan-McDermid syndrome features cognitive problems including absent speech in many cases. As the diagnosis is unfamiliar to most internists, the family asks for our help in bridging this knowledge gap by serving as a resource to the internist who will be coordinating the primary care for this young man. Since patients with Phelan-McDermid syndrome are generally medically healthy we broach the subject of what plans are in place for the likely possibility that he will outlive his parents.

As the day winds down, we see two cases in which management implications are at the forefront of the discussions. First a 40-year-old man with a lifelong diagnosis of Alport syndrome comes to see us because he needs assistance finding a suitable kidney donor. He had his first transplant more than a decade ago and is again requiring dialysis. His antibody status precludes most unrelated donors and the prime focus is on his sister who has a 50% chance of being an Alport carrier, which would render her unsuitable as a donor. Molecular genetic testing for X-linked Alport is now available in the United States and we make arrangements to use this to find his mutation and then hopefully exclude the mutation in his sister who is a willing donor.

Our final patient is a 29-year-old woman with Fabry’s disease, also X-linked, who is seeking advice on whether she needs to initiate treatment with recombinant enzyme replacement therapy. She has symptoms of pain in her hands and feet and early proteinuria; both findings suggesting microvascular disease caused by her Fabry’s. The mutation in her family also is quite severe, evidenced by others in the family history with severe problems. Based on these findings, we discuss the potential benefits of enzyme replacement therapy and initiate steps to start this therapy.

From these few cases referred to our genetics clinic by internists, it should be clear how far genetics has come, as well as how far it needs to go. Genetic counseling continues to hold value for patients and their families. The advent of hundreds of molecular tests has greatly improved our ability to accurately diagnose genetic conditions and increasingly we turn to our molecular tool boxes to reach a diagnosis, to guide medical management, and even to apply targeted therapy. To be sure, adult genetics clinics remain rare oddities, existing at only at a few academic medical centers. While we are only beginning to apply what we know about genetic medicine, I hope you found this brief glimpse at a "typical" day promising.

Dr. Taylor is associate professor in the department of internal medicine and director of adult clinical genetics at the University of Colorado at Denver.

I’d like to share how a "typical" clinic day goes for the patients that are referred to my adult genetic medicine practice.

Our first patient is our only return visit of the day and is a 54-year-old man with longstanding intellectual disability of unknown cause. Intellectual disabilities affect 1%-3% of persons and 10% of all families and represent a major public health problem. A significant proportion of cases are presumed to be genetic in etiology, although until relatively recently only a few (roughly 5%) could be diagnosed. Although children with intellectual problems are often evaluated by a comprehensive battery of testing, many adults are not evaluated, or were evaluated in the distant past.

A recent study (Genet. Med. 2010;12:32-8) in adults with unexplained intellectual disabilities found genetic diagnoses in more than 20% of patients and, while curative treatments are typically not possible, the value of a specific diagnosis to the patient’s family and the potential to access additional medical and social services with a confirmed diagnosis often make these investigations worthwhile. The recent development of X-linked "mental retardation" genetic panels that target men with intellectual disabilities will likely increase the diagnostic yield in this area.

Our second patient is a healthy 30-year-old man whose nephew was recently diagnosed with two genetic conditions: DiGeorge syndrome and I-cell disease. The patient and his wife, both present, want to know how this might affect their future children. We spend the first portion of the visit confirming the genetic and laboratory data surrounding the nephew’s unfortunate diagnoses. DiGeorge syndrome, which is caused by loss of genetic material from chromosome 22, is relatively common (1:4,000 infants), and frequently is identified because of cardiac defects, facial dysmorphisms, and learning difficulties. Milder cases might be missed in childhood and can present in adults as hypocalcemia, learning problems, and even schizophrenia. Only 10% of cases are inherited and our medical evaluation and physical exam did not turn up anything suspicious. We reassure the patient that his future children are at low risk for DiGeorge syndrome. I-cell disease, far less common (1:100,000), is unrelated to the DiGeorge diagnosis, but is uniformly fatal. We provide separate counseling for the I-cell risk and arrange for genetic testing to see if our patient is a carrier of an I-cell defect. If he is, his wife will then undergo carrier testing.

Our next patient is a 40-year-old woman with a history of joint hypermobility, chronic joint dislocations, easy bruising, and stretchy skin. Formerly very physically active, she had some pelvic symphysis separation during her last pregnancy and is now unable to work because of chronic pain. This constellation of symptoms represents one of the more-common referrals to adult medical geneticists. Our clinical evaluation confirms that she has a hypermobility syndrome, and we provide recommendations on how to best manage her pain and on a physical therapy regimen designed to improve her muscle tone and reduce the chance of future injuries.

Just before lunch, we have a heartbreaking visit with a 24-year-old woman who, accompanied by her partner and their young daughter, learns of her positive results for Huntington’s disease. At age 24 years, she has no overt symptoms, but the implications of the results are not lost on her as she cared for her grandparent who died from the disease. Furthermore, a psychiatric disorder in her estranged mother is now acknowledged as probable Huntington’s. The patient reveals to us that she is again pregnant and we have a long discussion about the potential risks to this pregnancy and what options she has to address this risk.

The afternoon begins with a full room; a 27-year-old man with Phelan-McDermid syndrome brought in by his parents and two caregivers. Phelan-McDermid syndrome represents one of a growing class of genetic diagnoses that have been recognized and defined only in the past 5-10 years. Involving a slightly different region of chromosome 22 than DiGeorge syndrome, Phelan-McDermid syndrome features cognitive problems including absent speech in many cases. As the diagnosis is unfamiliar to most internists, the family asks for our help in bridging this knowledge gap by serving as a resource to the internist who will be coordinating the primary care for this young man. Since patients with Phelan-McDermid syndrome are generally medically healthy we broach the subject of what plans are in place for the likely possibility that he will outlive his parents.

As the day winds down, we see two cases in which management implications are at the forefront of the discussions. First a 40-year-old man with a lifelong diagnosis of Alport syndrome comes to see us because he needs assistance finding a suitable kidney donor. He had his first transplant more than a decade ago and is again requiring dialysis. His antibody status precludes most unrelated donors and the prime focus is on his sister who has a 50% chance of being an Alport carrier, which would render her unsuitable as a donor. Molecular genetic testing for X-linked Alport is now available in the United States and we make arrangements to use this to find his mutation and then hopefully exclude the mutation in his sister who is a willing donor.

Our final patient is a 29-year-old woman with Fabry’s disease, also X-linked, who is seeking advice on whether she needs to initiate treatment with recombinant enzyme replacement therapy. She has symptoms of pain in her hands and feet and early proteinuria; both findings suggesting microvascular disease caused by her Fabry’s. The mutation in her family also is quite severe, evidenced by others in the family history with severe problems. Based on these findings, we discuss the potential benefits of enzyme replacement therapy and initiate steps to start this therapy.

From these few cases referred to our genetics clinic by internists, it should be clear how far genetics has come, as well as how far it needs to go. Genetic counseling continues to hold value for patients and their families. The advent of hundreds of molecular tests has greatly improved our ability to accurately diagnose genetic conditions and increasingly we turn to our molecular tool boxes to reach a diagnosis, to guide medical management, and even to apply targeted therapy. To be sure, adult genetics clinics remain rare oddities, existing at only at a few academic medical centers. While we are only beginning to apply what we know about genetic medicine, I hope you found this brief glimpse at a "typical" day promising.

Dr. Taylor is associate professor in the department of internal medicine and director of adult clinical genetics at the University of Colorado at Denver.