Genetic Diagnostic Yield Research Articles

Benefits of clinical criteria and high-throughput sequencing for diagnosing children with syndromic craniosynostosis

An accurate diagnosis of syndromic craniosynostosis (CS) is important for personalized treatment, surveillance, and genetic counselling. We describe detailed clinical criteria for syndromic CS and the distribution of genetic diagnoses within the cohort. The prospective registry of the Norwegian National Unit for Craniofacial Surgery was used to retrieve individuals with syndromic CS born between 1 January 2002 and 30 June 2019. All individuals were assessed by a clinical geneticist and classified using defined clinical criteria. A stepwise approach consisting of single-gene analysis, comparative genomic hybridization (aCGH), and exome-based high-throughput sequencing, first filtering for 72 genes associated with syndromic CS, followed by an extended trio-based panel of 1570 genes were offered to all syndromic CS cases. A total of 381 individuals were registered with CS, of whom 104 (27%) were clinically classified as syndromic CS. Using the single-gene analysis, aCGH, and custom-designed panel, a genetic diagnosis was confirmed in 73% of the individuals (n = 94). The diagnostic yield increased to 84% after adding the results from the extended trio-based panel. Common causes of syndromic CS were found in 53 individuals (56%), whereas 26 (28%) had other genetic syndromes, including 17 individuals with syndromes not commonly associated with CS. Only 15 individuals (16%) had negative genetic analyses. Using the defined combination of clinical criteria, we detected among the highest numbers of syndromic CS cases reported, confirmed by a high genetic diagnostic yield of 84%. The observed genetic heterogeneity encourages a broad genetic approach in diagnosing syndromic CS.

Clinical features and molecular genetics of patients with ABCA4-retinal dystrophies.

Pathogenic variations in the ABCA4 gene are a leading cause of vision loss in patients with inherited retinal diseases. ABCA4-retinal dystrophies are clinically heterogeneous, presenting with mild to severe degeneration of the retina. The purpose of this study was to clinically and genetically characterize patients with ABCA4-retinal dystrophies in Norway and describe phenotype-genotype associations. ABCA4 variants were detected in 111 patients with inherited retinal disease undergoing diagnostic genetic testing over a period of 12years. In patients where only a single ABCA4 variant was found, whole-gene ABCA4 sequencing was performed and intronic variants were investigated by mRNA analyses in fibroblasts. Medical journals were used to obtain a clinical description and ultrawidefield autofluorescence images were used to analyse retinal degeneration patterns. The genetic diagnostic yield was 89%. The intronic splice variant c.5461-10T>C was the most prevalent disease-causing variant (27%). Whole-gene ABCA4 sequencing detected two novel intronic variants (c.6729+81G>T and c.6817-679C>A) that we showed affected mRNA splicing. Peripheral retinal degeneration was identified in 33% of patients and was associated with genotypes that included severe loss of function variants. By contrast, peripheral degeneration was not found in patients with a disease duration over 20years and genotypes including p.(Asn1868lle), c.4253+43G>A or p.(Gly1961Glu) in trans with a loss of function variant. This study demonstrates the clinical and genetic heterogeneity of ABCA4-retinal dystrophies in Norway. Further, the study presents novel variants and increases our knowledge on phenotype-genotype associations and the presence of peripheral retinal degeneration in ABCA4-retinal dystrophy patients.

Genetic architecture of left ventricular noncompaction in adults

The genetic etiology and heritability of left ventricular noncompaction (LVNC) in adults is unclear. This study sought to assess the value of genetic testing in adults with LVNC. Adults diagnosed with LVNC while undergoing screening in the context of a family history of cardiomyopathy were excluded. Clinical data for 35 unrelated patients diagnosed with LVNC at ≥18 years of age were retrospectively analyzed. Left ventricular (LV) dysfunction, electrocardiogram (ECG) abnormalities, cardiac malformations or syndromic features were identified in 25 patients; 10 patients had isolated LVNC in the absence of cardiac dysfunction or syndromic features. Exome sequencing was performed, and analysis using commercial panels targeted 193 nuclear and mitochondrial genes. Nucleotide variants in coding regions or in intron-exon boundaries with predicted impacts on splicing were assessed. Fifty-four rare variants were identified in 35 nuclear genes. Across all 35 LVNC patients, the clinically meaningful genetic diagnostic yield was 9% (3/35), with heterozygous likely pathogenic or pathogenic variants identified in the NKX2-5 and TBX5 genes encoding cardiac transcription factors. No pathogenic variants were identified in patients with isolated LVNC in the absence of cardiac dysfunction or syndromic features. In conclusion, the diagnostic yield of genetic testing in adult index patients with LVNC is low. Genetic testing is most beneficial in LVNC associated with other cardiac and syndromic features, in which it can facilitate correct diagnoses, and least useful in adults with only isolated LVNC without a family history. Cardiac transcription factors are important in the development of LVNC and should be included in genetic testing panels.

The Feasibility and Outcomes of Genetic Testing for Autism and Neurodevelopmental Disorders on an Inpatient Child and Adolescent Psychiatry Service.

Diagnostic genetic testing is recommended for children with autism spectrum disorder and other neurodevelopmental disorders. One approach to improve access to genetic testing is to offer it on the inpatient child and adolescent psychiatry (CAP) service. We provided medical genetics education to CAP fellows and retrospectively compared the genetic testing rates and diagnostic yield pre- and post-education. We compared demographics to similar patients who received testing on other clinical services and assessed rates of outpatient genetics follow-up post-discharge. The genetic testing rate on the inpatient CAP service was 1.6% before the educational intervention and 10.7% afterward. Genetic risk factors were identified in 4.3% of inpatients. However, 34.8% had variants of unknown significance. 39.1% of patients who received genetic testing while inpatients were underrepresented minorities, compared to 7.7% of inpatients who received genetic testing from other clinical services. 43.5% of patients were lost to outpatient genetics follow-up. We have demonstrated that it is feasible to provide medical genetics education to CAP fellows on an inpatient service, which may improve genetic testing rates. This preliminary evidence also suggests that genetic testing for inpatients may identify variants of unknown significance instead of well-known neurodevelopmental disorder risk variants. Genetic testing on an inpatient CAP service may also improve access to genetic services for underrepresented minorities, but assuring outpatient follow-up can be challenging. LAY SUMMARY: Genetic testing is recommended for children with autism and related developmental conditions. We provided genetic testing to a group of these children who were in a psychiatric hospital by teaching their doctors how it can be helpful. We identified a genetic risk factor in a small percentage of children and a possible genetic risk factor in a large percentage of children. However, many children did not end up receiving their genetic test results once they left the hospital. These results tell us that the psychiatric hospital may be a good place for children with autism and behavioral problems to get genetic testing, but that it is really important that doctors assure follow-up is feasible for all patients to receive their genetic test results once they leave the hospital. Autism Res 2020, 13: 1450-1464. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.

Increasing the Genetic Diagnosis Yield in Inherited Retinal Dystrophies: Assigning Pathogenicity to Novel Non-canonical Splice Site Variants.

Aims: We aimed to validate the pathogenicity of genetic variants identified in inherited retinal dystrophy (IRD) patients, which were located in non-canonical splice sites (NCSS). Methods: After next generation sequencing (NGS) analysis (target gene panels or whole exome sequencing (WES)), NCSS variants were prioritized according to in silico predictions. In vivo and in vitro functional tests were used to validate their pathogenicity. Results: Four novel NCSS variants have been identified. They are located in intron 33 and 34 of ABCA4 (c.4774-9G>A and c.4849-8C>G, respectively), intron 2 of POC1B (c.101-3T>G) and intron 3 of RP2 (c.884-14G>A). Functional analysis detected different aberrant splicing events, including intron retention, exon skipping and intronic nucleotide addition, whose molecular effect was either the disruption or the elongation of the open reading frame of the corresponding gene. Conclusions: Our data increase the genetic diagnostic yield of IRD patients and expand the landscape of pathogenic variants, which will have an impact on the genotype–phenotype correlations and allow patients to opt for the emerging gene and cell therapies.

Robust Genetic Diagnosis of Split Hand-Foot Malformation by Exome Sequencing

ABSTRACT Purpose The present study aimed to evaluate the genetic diagnostic yield and accuracy of exome sequencing in Chinese patients with split hand–foot malformation (SHFM), a severe heterogeneous congenital anomaly characterized by hypodevelopment of the central ray of the hands and feet. Methods A cohort of seven families and five sporadic patients with SHFM was investigated. Genomic DNA was prepared from the peripheral blood of affected as well as unaffected individuals. Whole exome sequencing (WES) was performed to identify the pathogenic mutations. Array-based comparative genomic hybridization (aCGH), CytoScan, quantitative polymerase chain reaction (qPCR), and Sanger sequencing were performed to validate the findings of WES. WES data of an additional cohort of 24 patients with non-SHFM congenital hand anomalies were analyzed as the control. Results Pathogenic variants of TP63, c.G956A p.R319H, and c.T602A:p.L201H, were identified in two families by WES. In the remaining patients, copy number analysis of the WES data by XHMM software identified pathogenic 10q 24 duplication in five individuals from three families, which was further validated via CytoScan and qPCR; however, WES could not detect duplication in 10q24 in an additional cohort of 24 individuals with non-SHFM congenital hand anomaly. Importantly, qPCR analysis of the 10q24 region copy number revealed a definite consistency with WES data in all individuals. Genotype–phenotype analysis did not present any unique feature that could differentiate between the families with TP63 mutation and 10q24 duplication. Conclusions Our study demonstrated that WES is an accurate and sensitive method to detect the pathogenic 10q24 duplication. Collectively, with TP63 mutation, a single WES testing could yield a diagnosis rate of about 40% (5/12) for the SHFM patients, at least in our cohort. As the genotype–phenotype correlation remains unclear, WES could be used as a cost-effective method for the genetic diagnosis of SHFM.

Long-read nanopore sequencing resolves a TMEM231 gene conversion event causing Meckel-Gruber syndrome.

The diagnostic deployment of massively parallel short-read next-generation sequencing (NGS) has greatly improved genetic test availability, speed, and diagnostic yield, particularly for rare inherited disorders. Nonetheless, diagnostic approaches based on short-read sequencing have a poor ability to accurately detect gene conversion events. We report on the genetic analysis of a family in which 3 fetuses had clinical features consistent with the autosomal recessive disorder Meckel-Gruber syndrome (MKS). Targeted NGS of 29 known MKS-associated genes revealed a heterozygous TMEM231 splice donor variant c.929+1A>G. Comparative read-depth analysis, performed to identify a second pathogenic allele, revealed an apparent heterozygous deletion of TMEM231 exon 4. To verify this result we performed single-molecule long-read sequencing of a long-range polymerase chain reaction product spanning this locus. We identified four missense variants that were absent from the short-read dataset due to the preferential mapping of variant-containing reads to a downstream TMEM231 pseudogene. Consistent with the parental segregation analysis, we demonstrate that the single-molecule long reads could be used to show that the variants are arranged in trans. Our experience shows that robust validation of apparent dosage variants remains essential to avoid the pitfalls of short-read sequencing and that new third-generation long-read sequencing technologies can already aid routine clinical care.

A mutation creating an upstream translation initiation codon in SLC22A5 5'UTR is a frequent cause of primary carnitine deficiency.

Primary carnitine deficiency is caused by a defect in the active cellular uptake of carnitine by Na+‐dependent organic cation transporter novel 2 (OCTN2). Genetic diagnostic yield for this metabolic disorder has been relatively low, suggesting that disease‐causing variants are missed. We Sanger sequenced the 5′ untranslated region (UTR) of SLC22A5 in individuals with possible primary carnitine deficiency in whom no or only one mutant allele had been found. We identified a novel 5′‐UTR c.‐149G>A variant which we characterized by expression studies with reporter constructs in HeLa cells and by carnitine‐transport measurements in fibroblasts using a newly developed sensitive assay based on tandem mass spectrometry. This variant, which we identified in 57 of 236 individuals of our cohort, introduces a functional upstream out‐of‐frame translation initiation codon. We show that the codon suppresses translation from the wild‐type ATG of SLC22A5, resulting in reduced OCTN2 protein levels and concomitantly lower transport activity. With an allele frequency of 24.2% the c.‐149G>A variant is the most frequent cause of primary carnitine deficiency in our cohort and may explain other reported cases with an incomplete genetic diagnosis. Individuals carrying this variant should be clinically re‐evaluated and monitored to determine if this variant has clinical consequences.

Chromosomal microarray analysis in fetuses with an isolated congenital heart defect: A retrospective, nationwide, multicenter study in France.

Congenital heart defects (CHDs) may be isolated or associated with other malformations. The use of chromosome microarray (CMA) can increase the genetic diagnostic yield for CHDs by between 4% and 10%. The objective of this study was to evaluate the value of CMA after the prenatal diagnosis of an isolated CHD. In a retrospective, nationwide study performed in France, we collected data on all cases of isolated CHD that had been explored using CMAs in 2015. A total of 239 fetuses were included and 33 copy number variations (CNVs) were reported; 19 were considered to be pathogenic, six were variants of unknown significance, and eight were benign variants. The anomaly detection rate was 10.4% overall but ranged from 0% to 16.7% as a function of the isolated CHD in question. The known CNVs were 22q11.21 deletions (n=10), 22q11.21 duplications (n=2), 8p23 deletions (n=2), an Alagille syndrome (n=1), and a Kleefstra syndrome (n=1). The additional diagnostic yield was clinically significant (3.1%), even when anomalies in the 22q11.21 region were not taken into account. Hence, patients with a suspected isolated CHD and a normal karyotype must be screened for chromosome anomalies other than 22q11.21 duplications and deletions.

The added value of WES reanalysis in the field of genetic diagnosis: lessons learned from 200 exomes in the Lebanese population

BackgroundThe past few decades have witnessed a tremendous development in the field of genetics. The implementation of next generation sequencing (NGS) technologies revolutionized the field of molecular biology and made the genetic information accessible at a large scale. However, connecting a rare genetic variation to a complex phenotype remains challenging. Indeed, identifying the cause of a genetic disease requires a multidisciplinary approach, starting with the establishment of a clear phenotype with a detailed family history and ending, in some cases, with functional assays that are crucial for the validation of the pathogenicity of a mutation.MethodsTwo hundred Lebanese patients, presenting a wide spectrum of genetic disorders (neurodevelopmental, neuromuscular or metabolic disorders, etc.), sporadic or inherited, dominant or recessive, were referred, over the last three and a half years, to the Medical Genetics Unit (UGM) of Saint Joseph University (USJ). In order to identify the genetic basis of these diseases, Whole Exome Sequencing (WES), followed by a targeted analysis, was performed for each case. In order to improve the genetic diagnostic yield, WES data, generated during the first 2 years of this study, were reanalyzed for all patients who were left undiagnosed at the genetic level. Reanalysis was based on updated bioinformatics tools and novel gene discoveries.ResultsOur initial analysis allowed us to identify the specific genetic mutation causing the disease in 49.5% of the cases, in line with other international studies. Repeated WES analysis enabled us to increase the diagnostics yield to 56%.ConclusionThe present article reports the detailed results of both analysis and pinpoints the contribution of WES data reanalysis to an efficient genetic diagnosis. Lessons learned from WES reanalysis and interpretation are also shared.

SU46 - PSYCHIATRIC GENETIC COUNSELING: CHALLENGES IN AUTISM SPECTRUM DISORDERS

Autism Spectrum Disorders (ASD) have one of the highest estimates of heritability among psychiatric conditions. Genetic testing is now considered standard of care for diagnosis of ASD etiology, and is increasingly available, affordable, and offered to patients and their families. The 2013 American College of Medical Genetics Practice Guidelines estimates a genetic diagnostic yield of 30–40% in ASD cases, recommending Chromosome Microarray (CMA), single gene testing such as FMR1, as well as other testing such as metabolic studies. As of 2017, more than 20 academic and commercial laboratories have developed clinical genetic tests specific for ASD, which are being marketed as diagnostic testing to clinicians worldwide. However, these gene panels often have low clinical validity, and often include genes where the associations between the loci and ASD are unclear. Little is known regarding the practical experience of individuals with ASD undergoing genetic testing. Here, we present five illustrative cases and suggest standardized approaches for genetic counseling in ASD. Since 2013, clinical genetic testing has been routinely offered to individuals with ASD in our Genetics clinic. The most common test offered was CMA, followed by FMR1 and whole exome sequencing. Through retrospective chart review, five representative cases were selected to highlight the diagnostic and counseling complexities. From 2013 to 2016, we provided genetic counseling to 29 individuals with ASD, resulting in at least a partial genetic diagnosis in 34% of cases, a variant of unknown significance in 10% of cases, and incidental findings in 7% of cases. We present five cases of nonsyndromic ASD with variable genetic testing results (1q21.1 deletion, 16p11.2 duplication, 15q13.3 duplication, AUTS2, 47, XYY) and discuss the genetic counseling issues for each. In our collective experience with these and other cases, we have found that diagnostic challenges include phenotypic and locus heterogeneity, variable expressivity, reduced penetrance, causative versus risk alleles, and changing genetic associations as research progresses. Psychosocial challenges include misleading information online, illness representation beliefs of patients and families, stigma, guilt and shame, and family communication. It is not enough to know that certain genetic factors are associated with ASD. Translating this information in a meaningful way for patients and families is the ultimate goal of all clinically-directed research. The reactions of the families described in this case series illustrate these challenges. We recommend standardizing informed consent for genetic testing in ASD, especially regarding the inherent uncertainties, and to include referral to a clinical genetic specialist if available. Careful and informed genetic counseling is crucial and may lead to improved coping and adaptation, and may reduce negative consequences of stigma and discrimination.

Utility and implications of exome sequencing in early-onset Parkinson's disease.

Although the genetic load is high in early-onset Parkinson's disease, thorough investigation of the genetic diagnostic yield has yet to be established. The objectives of this study were to assess variants in known genes for PD and other movement disorders and to find new candidates in 50 patients with early-onset PD. We searched for variants either within genes listed by the International Parkinson and Movement Disorder Society Task Force on Genetic Nomenclature or rare homozygous variants in novel candidate genes. Further, exome data from 1148 European PD patients (International Parkinson Disease Genomics Consortium) were used for association testing. Seven patients (14%) carried pathogenic or likely pathogenic variants in Parkin, PLA2G6, or GBA. In addition, rare missense variants in DNAJC13:p.R1830C and in PPM1K:p.Y352C were detected. SPG7:p.A510V and PPM1K:p.Y352C revealed significant association with PD risk (P < 0.05). Although we identified pathogenic variants in 14% of our early-onset PD patients, the majority remain unexplained, and novel candidates need to be validated independently to better further evaluate their role in PD. © 2018 International Parkinson and Movement Disorder Society.

Genetic profile and clinical application of chromosomal microarray in children with intellectual disability in Hong Kong.

Chromosomal microarray (CMA) is recommended as a first-tier genetic investigation for intellectual disability (ID), developmental delay, or autism spectrum disorder due to its higher diagnostic yield with respect to conventional karyotyping. The aim of the present study was to investigate the genetic profile and diagnostic yield of CMA in children with moderate, severe and profound ID. A pilot cross-sectional study was performed by the Child Assessment Service and the Clinical Genetic Service in Hong Kong from July 2016 to June 2017. Children with unexplained ID were recruited for CMA testing by an expedited referral pathway. Children who were existing clients of the Clinical Genetic Service were also recruited. Of 225 children included in this study, 68 (30.2%) had genetic diagnoses. Among the 138 children who underwent CMA testing, 53 (38%) children were referred to the Clinical Genetic Service by the expedited referral pathway. The respective diagnostic yields of CMA in moderate, severe, and profound ID were 8.7%, 17.6%, and 23.5% (P<0.05). Children with dysmorphic features demonstrated a much higher yield from CMA (45.8% vs 4.4%, P<0.05). CONCLUSTION. The overall diagnostic yield (11.6%) of CMA in this cohort is comparable with that of other international cohorts. This further supports the use of CMA as a first-tier genetic investigation for children with ID, developmental delay, or autism spectrum disorder, particularly for those with severe disease.

Genetic test utilization and diagnostic yield in adult patients with neurological disorders.

To determine the diagnostic yield of different genetic test modalities in adult patients with neurological disorders, we evaluated all adult patients seen for genetic diagnostic evaluation in the outpatient neurology practice at the University of Pennsylvania between January 2016 and April 2017 as part of the newly created Penn Neurogenetics Program. Subjects were identified through our electronic medical system as those evaluated by the Program's single clinical genetic counselor in that period. A total of 377 patients were evaluated by the Penn Neurogenetics Program in different settings and genetic testing recommended. Of those, 182 (48%) were seen in subspecialty clinic setting and 195 (52%) in a General Neurogenetics Clinic. Genetic testing was completed in over 80% of patients in whom it was recommended. The diagnostic yield was 32% across disease groups. Stratified by testing modality, the yield was highest with directed testing (50%) and array comparative genomic hybridization (45%), followed by gene panels and exome testing (25% each). In conclusion, genetic testing can be successfully requested in clinic in a large majority of adult patients. Age is not a limiting factor for a genetic diagnostic evaluation and the yield of clinical testing across phenotypes (almost 30%) is consistent with previous phenotype-focused or research-based studies. These results should inform the development of specific guidelines for clinical testing and serve as evidence to improve reimbursement by insurance payers.

Association between mutation status and left ventricular reverse remodelling in dilated cardiomyopathy

ObjectiveTo explore the genetic landscape of a well selected dilated cardiomyopathy (DCM) cohort, assessing the possible relation between different genotypes and left ventricular reverse remodelling (LVRR).MethodsA cohort of 152 patients...

Diagnostic yield of genetic testing in epileptic encephalopathy in childhood.

Epilepsy is a common neurologic disorder of childhood. To determine the genetic diagnostic yield in epileptic encephalopathy, we performed a retrospective cohort study in a single epilepsy genetics clinic. We included all patients with intractable epilepsy, global developmental delay, and cognitive dysfunction seen between January 2012 and June 2014 in the Epilepsy Genetics Clinic. Electronic patient charts were reviewed for clinical features, neuroimaging, biochemical investigations, and molecular genetic investigations including targeted next-generation sequencing of epileptic encephalopathy genes. Genetic causes were identified in 28% of the 110 patients: 7% had inherited metabolic disorders including pyridoxine dependent epilepsy caused by ALDH7A1 mutation, Menkes disease, pyridox(am)ine-5-phosphate oxidase deficiency, cobalamin G deficiency, methylenetetrahydrofolate reductase deficiency, glucose transporter 1 deficiency, glycine encephalopathy, and pyruvate dehydrogenase complex deficiency; 21% had other genetic causes including genetic syndromes, pathogenic copy number variants on array comparative genomic hybridization, and epileptic encephalopathy related to mutations in the SCN1A, SCN2A, SCN8A, KCNQ2, STXBP1, PCDH19, and SLC9A6 genes. Forty-five percent of patients obtained a genetic diagnosis by targeted next-generation sequencing epileptic encephalopathy panels. It is notable that 4.5% of patients had a treatable inherited metabolic disease. To the best of our knowledge, this is the first study to combine inherited metabolic disorders and other genetic causes of epileptic encephalopathy. Targeted next-generation sequencing panels increased the genetic diagnostic yield from <10% to >25% in patients with epileptic encephalopathy.

Diagnostic yield, interpretation, and clinical utility of mutation screening of sarcomere encoding genes in Danish hypertrophic cardiomyopathy patients and relatives.

The American Heart Association (AHA) recommends family screening for hypertrophic cardiomyopathy (HCM). We assessed the outcome of family screening combining clinical evaluation and screening for sarcomere gene mutations in a cohort of 90 Danish HCM patients and their close relatives, in all 451 persons. Index patients were screened for mutations in all coding regions of 10 sarcomere genes (MYH7, MYL3, MYBPC3, TNNI3, TNNT2, TPM1, ACTC, CSRP3, TCAP, and TNNC1) and five exons of TTN. Relatives were screened for presence of minor or major diagnostic criteria for HCM and tracking of DNA variants was performed. In total, 297 adult relatives (>18 years) (51.2%) fulfilled one or more criteria for HCM. A total of 38 HCM-causing mutations were detected in 32 index patients. Six patients carried two disease-associated mutations. Twenty-two mutations have only been identified in the present cohort. The genetic diagnostic yield was almost twice as high in familial HCM (53%) vs. HCM of sporadic or unclear inheritance (19%). The yield was highest in families with an additional history of HCM-related clinical events. In relatives, 29.9% of mutation carriers did not fulfil any clinical diagnostic criterion, and in 37.5% of relatives without a mutation, one or more criteria was fulfilled. A total of 60% of family members had no mutation and could be reassured and further follow-up ceased. Genetic diagnosis may be established in approximately 40% of families with the highest yield in familial HCM with clinical events. Mutation-screening was superior to clinical investigation in identification of individuals not at increased risk, where follow-up is redundant, but should be offered in all families with relatives at risk for developing HCM.