Lora J. H. Bean

Ethnicity, sex, and the incidence of congenital heart defects: a report from the National Down Syndrome Project

Purpose: The population-based National Down Syndrome Project combined epidemiological and molecular methods to study congenital heart defects in Down syndrome.Methods: Between 2000 and 2004, six sites collected DNA, clinical, and epidemiological information on parents and infants. We used logistic regression to examine factors associated with the most common Down syndrome-associated heart defects.Results: Of 1469 eligible infants, major cardiac defects were present in 44%; atrioventricular septal defect (39%), secundum atrial septal defect (42%), ventricular septal defect (43%), and tetralogy of Fallot (6%). Atrioventricular septal defects showed the most significant sex and ethnic differences with twice as many affected females (odds ratio, 1.93; 95% confidence interval, 1.40–2.67) and, compared with whites, twice as many blacks (odds ratio, 2.06; 95% confidence interval, 1.32–3.21) and half as many Hispanics (odds ratio, 0.48; 95% confidence interval, 0.30–0.77). No associations were found with origin of the nondisjunction error or with the presence of gastrointestinal defects.Conclusions: Sex and ethnic differences exist for atrioventricular septal defects in Down syndrome. Identification of genetic and environmental risk factors associated with these differences is essential to our understanding of the etiology of congenital heart defects.

ACMG position statement on prenatal/preconception expanded carrier screening.

For years, clinicians have offered gene-by-gene carrier screening to patients and couples considering future pregnancy or those with an ongoing pregnancy early in gestation. Examples include ethnic-specific screening offered to Ashkenazi Jewish patients and panethnic screening for cystic fibrosis and spinal muscular atrophy. Next-generation sequencing methods now available permit screening for many more disorders with high fidelity, quick turnaround time, and lower costs. However, instituting these technologies carries with it perils that must be addressed. The basis for the selection of disorders on expanded carrier screening panels should be disclosed. The information provided about disorders with mild phenotypes, variable expression, low penetrance, and/or characterized by an adult onset should be complete and transparent, allowing patients to opt out of receiving these test results. Patients also must be made aware of the concept of residual risk following negative test results. Laboratories have a duty to participate in and facilitate this information transfer.Genet Med 2013:15(6):482–483

A comprehensive genomic approach for neuromuscular diseases gives a high diagnostic yield

Neuromuscular diseases (NMDs) are a group of >200 highly genetically as well as clinically heterogeneous inherited genetic disorders that affect the peripheral nervous and muscular systems, resulting in gross motor disability. The clinical and genetic heterogeneities of NMDs make disease diagnosis complicated and expensive, often involving multiple tests.

Variation in folate pathway genes contributes to risk of congenital heart defects among individuals with Down syndrome

Cardiac abnormalities are one of the most common congenital defects observed in individuals with Down syndrome. Considerable research has implicated both folate deficiency and genetic variation in folate pathway genes with birth defects, including both congenital heart defects (CHD) and Down syndrome (DS). Here, we test variation in folate pathway genes for a role in the major DS‐associated CHD atrioventricular septal defect (AVSD). In a group of 121 case families (mother, father, and proband with DS and AVSD) and 122 control families (mother, father, and proband with DS and no CHD), tag SNPs were genotyped in and around five folate pathway genes: 5,10‐methylenetetrahyrdofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), cystathionine β‐synthase (CBS), and the reduced folate carrier (SLC19A1, RFC1). SLC19A1 was found to be associated with AVSD using a multilocus allele‐sharing test. Individual SNP tests also showed nominally significant associations with odds ratios of between 1.34 and 3.78, depending on the SNP and genetic model. Interestingly, all marginally significant SNPs in SLC19A1 are in strong linkage disequilibrium (r2≥0.8) with the nonsynonymous coding SNP rs1051266 (c.80A>G), which has previously been associated with nonsyndromic cases of CHD. In addition to SLC19A1, the known functional polymorphism MTHFR c.1298A was over‐transmitted to cases with AVSD (P=0.05) and under‐transmitted to controls (P=0.02). We conclude, therefore, that disruption of the folate pathway contributes to the incidence of AVSD among individuals with DS. Genet. Epidemiol. 34: 603–612, 2010.

An Excess of Deleterious Variants in VEGF-A Pathway Genes in Down-Syndrome-Associated Atrioventricular Septal Defects

About half of people with trisomy 21 have a congenital heart defect (CHD), whereas the remainder have a structurally normal heart, demonstrating that trisomy 21 is a significant risk factor but is not causal for abnormal heart development. Atrioventricular septal defects (AVSD) are the most commonly occurring heart defects in Down syndrome (DS), and ∼65% of all AVSD is associated with DS. We used a candidate-gene approach among individuals with DS and complete AVSD (cases = 141) and DS with no CHD (controls = 141) to determine whether rare genetic variants in genes involved in atrioventricular valvuloseptal morphogenesis contribute to AVSD in this sensitized population. We found a significant excess (p < 0.0001) of variants predicted to be deleterious in cases compared to controls. At the most stringent level of filtering, we found potentially damaging variants in nearly 20% of cases but fewer than 3% of controls. The variants with the highest probability of being damaging in cases only were found in six genes: COL6A1, COL6A2, CRELD1, FBLN2, FRZB, and GATA5. Several of the case-specific variants were recurrent in unrelated individuals, occurring in 10% of cases studied. No variants with an equal probability of being damaging were found in controls, demonstrating a highly specific association with AVSD. Of note, all of these genes are in the VEGF-A pathway, even though the candidate genes analyzed in this study represented numerous biochemical and developmental pathways, suggesting that rare variants in the VEGF-A pathway might contribute to the genetic underpinnings of AVSD in humans.

CRELD1 mutations contribute to the occurrence of cardiac atrioventricular septal defects in down syndrome

Cheryl L. Maslen,* Darcie Babcock, Susan W. Robinson, Lora J.H. Bean, Kenneth J. Dooley, Virginia L. Willour, and Stephanie L. Sherman Department of Medicine, Division of Endocrinology, Oregon Health & Science University, Portland, Oregon Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon Heart Research Center, Oregon Health & Science University, Portland, Oregon Department of Human Genetics, Emory University, Atlanta, Georgia Department of Pediatrics, Sibley Heart Center, Cardiology, Children’s Healthcare of Atlanta, Emory University, Atlanta, Georgia Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, Maryland

Targeted comparative genomic hybridization array for the detection of single- and multiexon gene deletions and duplications

Purpose: To develop a high resolution microarray based method to detect single- and multiexons gene deletions and duplications.Methods: We have developed a high-resolution comparative genomic hybridization array to detect single- and multiexon deletions and duplications in a large set of genes on a single microarray, using the NimbleGen 385K array with an exon-centric design.Results: We have successfully developed, validated, and implemented a targeted gene comparative genomic hybridization arrays for detecting single- and multiexon deletions and duplication in autosomal and X-linked disease-associated genes.Conclusion: The comparative genomic hybridization arrays can be adopted readily by clinical molecular diagnostic laboratories as a rapid, cost-effective, highly sensitive, and accurate approach for the detection of single- and multiexon deletions or duplications, particularly in cases where direct sequencing fails to identify a mutation.

Free the Data: One Laboratory's Approach to Knowledge-Based Genomic Variant Classification and Preparation for EMR Integration of Genomic Data

Current technology allows clinical laboratories to rapidly translate research discoveries from small patient cohorts into clinical genetic tests; therefore, a potentially large proportion of sequence variants identified in individuals with clinical features of a genetic disorder remain unpublished. Without a mechanism for clinical laboratories to share data, interpretation of sequence variants may be inconsistent. We describe here the two components of Emory Genetics Laboratorys (EGL) in‐house developed data management system. The first is a highly curated variant database with a data structure designed to facilitate sharing of information about variants identified at EGL with curated databases. This system also tracks changes in variant classifications, creating a record of previous cases in need of updated reports when a classification is changed. The second component, EmVClass, is a Web‐based interface that allows any user to view the inventory of variants classified at EGL. These software tools provide a solution to two pressing issues faced by clinical genetics laboratories: how to manage a large variant inventory with evolving variant classifications that need to be communicated to healthcare providers and how to make that inventory of variants freely available to the community.

Genetic Screening for OPA1 and OPA3 Mutations in Patients with Suspected Inherited Optic Neuropathies

PURPOSE Autosomal-dominant optic atrophy (DOA) is one of the most common inherited optic neuropathies, and it is genetically heterogeneous, with mutations in both OPA1 and OPA3 known to cause disease. Approximately 60% of cases harbor OPA1 mutations, whereas OPA3 mutations have been reported in only 2 pedigrees with DOA and premature cataracts. The aim of this study was to determine the yield of OPA1 and OPA3 screening in a cohort of presumed DOA cases referred to a tertiary diagnostic laboratory. DESIGN Retrospective case series. PARTICIPANTS One hundred eighty-eight probands with bilateral optic atrophy referred for molecular genetic investigations at a tertiary diagnostic facility: 38 patients with an autosomal-dominant pattern of inheritance and 150 sporadic cases. METHODS OPA1 and OPA3 genetic testing was initially performed using polymerase chain reaction-based sequencing methods. The presence of large-scale OPA1 and OPA3 genomic rearrangements was assessed further with a targeted comparative genomic hybridization microarray platform. The 3 primary Leber hereditary optic neuropathy (LHON) mutations, m.3460G→>A, m.11778G→A, and m.14484T→C, also were screened in all patients. MAIN OUTCOME MEASURES The proportion of patients with OPA1 and OPA3 pathogenic mutations. The clinical profile observed in molecularly confirmed DOA cases. RESULTS Twenty-one different OPA1 mutations were found in 27 (14.4%) of the 188 probands screened. The mutations included 6 novel pathogenic variants and the first reported OPA1 initiation codon mutation at c.1A→T. An OPA1 missense mutation, c.239A→G (p.Y80C), was identified in an 11-year-old black girl with optic atrophy and peripheral sensorimotor neuropathy in her lower limbs. The OPA1 detection rate was significantly higher among individuals with a positive family history of visual failure (50.0%) compared with sporadic cases (5.3%). The primary LHON screen was negative in the patient cohort, and additional molecular investigations did not reveal any large-scale OPA1 rearrangements or OPA3 genetic defects. The mean baseline visual acuity for the OPA1-positive group was 0.48 logarithm of the minimum angle of resolution (units mean Snellen equivalent, 20/61; range, 20/20-20/400; 95% confidence interval, 20/52-20/71), and visual deterioration occurred in 54.2% of patients during follow-up. CONCLUSIONS OPA1 mutations are the most common genetic defects identified in patients with suspected DOA, whereas OPA3 mutations are very rare in isolated optic atrophy cases.

Lack of maternal folic acid supplementation is associated with heart defects in Down syndrome: a report from the National Down Syndrome Project

BACKGROUND Maternal folic acid supplementation has been associated with a reduced risk for neural tube defects and may be associated with a reduced risk for congenital heart defects and other birth defects. Individuals with Down syndrome are at high risk for congenital heart defects and have been shown to have abnormal folate metabolism. METHODS As part of the population-based case-control National Down Syndrome Project, 1011 mothers of infants with Down syndrome reported their use of supplements containing folic acid. These data were used to determine whether a lack of periconceptional maternal folic acid supplementation is associated with congenital heart defects in Down syndrome. We used logistic regression to test the relationship between maternal folic acid supplementation and the frequency of specific heart defects correcting for maternal race or ethnicity, proband sex, maternal use of alcohol and cigarettes, and maternal age at conception. RESULTS Lack of maternal folic acid supplementation was more frequent among infants with Down syndrome and atrioventricular septal defects (odds ratio [OR], 1.69; 95% confidence interval [CI], 1.08-2.63; p = 0.011) or atrial septal defects (OR, 1.69; 95% CI, 1.11-2.58; p = 0.007) than among infants with Down syndrome and no heart defect. Preliminary evidence suggests that the patterns of association differ by race or ethnicity and sex of the proband. There was no statistically significant association with ventricular septal defects (OR, 1.26; 95% CI, 0.85-1.87; p = 0.124). CONCLUSIONS Our results suggest that lack of maternal folic acid supplementation is associated with septal defects in infants with Down syndrome. Birth Defects Research (Part A), 2011.