scholarly journals Pathogenic ASXL1 somatic variants in reference databases complicate germline variant interpretation for Bohring-Opitz Syndrome

2016 ◽  
Author(s):  
Colleen M. Carlston ◽  
Anne H. O’Donnell-Luria ◽  
Hunter R. Underhill ◽  
Beryl B. Cummings ◽  
Ben Weisburd ◽  
...  
Keyword(s):  
Somatic Mosaicism ◽  
Failure To Thrive ◽  
Reference Population ◽  
Global Developmental Delay ◽  
Pathogenic Variants ◽  
Exome Aggregation Consortium ◽  
Reference Databases ◽  
Opitz Syndrome ◽  
Reduced Penetrance ◽  
Population Databases

ABSTRACTThe interpretation of genetic variants identified during clinical sequencing has come to rely heavily on reference population databases such as the Exome Aggregation Consortium (ExAC). Genuinely pathogenic variants, particularly in genes associated with severe autosomal dominant conditions, are assumed to be absent or extremely rare in these databases. Clinical exome sequencing of a six-year-old female patient with seizures, global developmental delay, dysmorphic features and failure to thrive identified an ASXL1 variant that was previously reported as causative of Bohring-Opitz syndrome (BOS). Surprisingly, the variant was observed seven times in the ExAC database, presumably in individuals without BOS. Although the BOS phenotype matched the presentation of the patient, the presence of the variant in reference population databases introduced ambiguity in result interpretation. Interrogation of the literature revealed that acquired somatic mosaicism of ASXL1 variants (including known pathogenic variants) during hematopoietic clonal expansion may be concomitant with aging in healthy individuals. We examined all high quality ASXL1 predicted truncating variant calls in the ExAC database and determined the majority could be attributed to this phenomenon. Failure to consider somatic mosaicism may lead to the inaccurate assumption that conditions like Bohring-Opitz syndrome have reduced penetrance, or the misclassification of potentially pathogenic variants.

scholarly journals Unsuspected somatic mosaicism for FBN1 gene contributes to Marfan syndrome

2021 ◽  
Author(s):  
Pauline Arnaud ◽  
Hélène Morel ◽  
Olivier Milleron ◽  
Laurent Gouya ◽  
Christine Francannet ◽  
...  
Keyword(s):  
Marfan Syndrome ◽  
Somatic Mosaicism ◽  
Variant Calling ◽  
Copy Number Variations ◽  
Pathogenic Variant ◽  
Single Nucleotide Variants ◽  
Bioinformatics Analyses ◽  
Single Nucleotide ◽  
Fbn1 Gene ◽  
Pathogenic Variants

Abstract Purpose Individuals with mosaic pathogenic variants in the FBN1 gene are mainly described in the course of familial screening. In the literature, almost all these mosaic individuals are asymptomatic. In this study, we report the experience of our team on more than 5,000 Marfan syndrome (MFS) probands. Methods Next-generation sequencing (NGS) capture technology allowed us to identify five cases of MFS probands who harbored a mosaic pathogenic variant in the FBN1 gene. Results These five sporadic mosaic probands displayed classical features usually seen in Marfan syndrome. Combined with the results of the literature, these rare findings concerned both single-nucleotide variants and copy-number variations. Conclusion This underestimated finding should not be overlooked in the molecular diagnosis of MFS patients and warrants an adaptation of the parameters used in bioinformatics analyses. The five present cases of symptomatic MFS probands harboring a mosaic FBN1 pathogenic variant reinforce the fact that apparently asymptomatic mosaic parents should have a complete clinical examination and a regular cardiovascular follow-up. We advise that individuals with a typical MFS for whom no single-nucleotide pathogenic variant or exon deletion/duplication was identified should be tested by NGS capture panel with an adapted variant calling analysis.

Molecular Analysis of the CYP11B2 Gene in 62 Patients with Hypoaldosteronism Due to Aldosterone Synthase Deficiency

2020 ◽  
Vol 106 (1) ◽  
pp. e182-e191
Author(s):  
Christina Merakou ◽  
Irene Fylaktou ◽  
Amalia Sertedaki ◽  
Maria Dracopoulou ◽  
Antonis Voutetakis ◽  
...  
Keyword(s):  
Gene Sequencing ◽  
Failure To Thrive ◽  
In Silico Analysis ◽  
Autosomal Recessive Disorder ◽  
Molecular Study ◽  
Aldosterone Synthase ◽  
Salt Wasting ◽  
Pathogenic Variants ◽  
Novel Variants ◽  
Aldosterone Synthase Deficiency

Abstract Context Isolated congenital hypoaldosteronism presents in early infancy with symptoms including vomiting, severe dehydration, salt wasting, and failure to thrive. The main causes of this rare autosomal recessive disorder is pathogenic variants of the CYP11B2 gene leading to aldosterone synthase deficiency. Objective To investigate the presence of CYP11B2 pathogenic variants in a cohort of patients with a clinical, biochemical, and hormonal profile suggestive of aldosterone synthase deficiency. Design Clinical and molecular study. Setting Tertiary academic Children’s Hospital, Center for Rare Pediatric Endocrine Diseases. Patients and Methods Sixty-two patients (56 unrelated patients and 6 siblings), with hypoaldosteronism and their parents, underwent CYP11B2 gene sequencing after its selective amplification against the highly homologous CYP11B1 gene. In silico analysis of the identified novel variants was carried out to evaluate protein stability and potential pathogenicity. Results CYP11B2 gene sequencing revealed that 62 patients carried a total of 12 different pathogenic CYP11B2 gene variants, 6 of which are novel. Importantly, 96% of the 56 patients carried the previously reported p.T185I variant either in homozygosity or in compound heterozygosity with another variant. The 6 novel variants detected were: p.M1I, p.V129M, p.R141Q, p.A165T, p.R448C, and the donor splice site variant of intron 8, c.1398 + 1G > A. Conclusion Molecular diagnosis was achieved in 62 patients with aldosterone synthase deficiency, the largest cohort thus far reported. Six novel genetic variants were identified as possibly pathogenic, extending the spectrum of reported molecular defects of the CYP11B2 gene.

scholarly journals Expansion and further delineation of the SETD5 phenotype leading to global developmental delay, variable dysmorphic features, and reduced penetrance

2018 ◽  
Vol 93 (4) ◽  
pp. 752-761 ◽  
Author(s):  
Z. Powis ◽  
K.D. Farwell Hagman ◽  
C. Mroske ◽  
K. McWalter ◽  
J.S. Cohen ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Global Developmental Delay ◽  
Dysmorphic Features ◽  
Reduced Penetrance

scholarly journals Inherited variants in CHD3 demonstrate variable expressivity in Snijders Blok-Campeau syndrome

2021 ◽  
Author(s):  
Jet van der Spek ◽  
Joery den Hoed ◽  
Lot Snijders Blok ◽  
Alexander J. M. Dingemans ◽  
Dick Schijven ◽  
...  
Keyword(s):  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Underlying Mechanism ◽  
Next Generation Sequencing Data ◽  
Sequencing Data ◽  
Human Phenotype ◽  
Variable Expressivity ◽  
Pathogenic Variants ◽  
Reduced Penetrance ◽  
Coding Variants

Interpretation of next-generation sequencing data of individuals with an apparent sporadic neurodevelopmental disorder (NDD) often focusses on pathogenic variants in genes associated with NDD, assuming full clinical penetrance with limited variable expressivity. Consequently, inherited variants in genes associated with dominant disorders may be overlooked when the transmitting parent is clinically unaffected. While de novo variants explain a substantial proportion of cases with NDDs, a significant number remains undiagnosed possibly explained by coding variants associated with reduced penetrance and variable expressivity. We characterized twenty families with inherited heterozygous missense or protein-truncating variants (PTVs) in CHD3, a gene in which de novo variants cause Snijders Blok-Campeau syndrome, characterized by intellectual disability, speech delay and recognizable facial features (SNIBCPS). Notably, the majority of the inherited CHD3 variants were maternally transmitted. Computational facial and human phenotype ontology-based comparisons demonstrated that the phenotypic features of probands with inherited CHD3 variants overlap with the phenotype previously associated with de novo variants in the gene, while carrier parents are mildly or not affected, suggesting variable expressivity. Additionally, similarly reduced expression levels of CHD3 protein in cells of an affected proband and of related healthy carriers with a CHD3 PTV, suggested that compensation of expression from the wildtype allele is unlikely to be an underlying mechanism. Our results point to a significant role of inherited variation in SNIBCPS, a finding that is critical for correct variant interpretation and genetic counseling and warrants further investigation towards understanding the broader contributions of such variation to the landscape of human disease.

Phenotype Analysis and Genetic Study of Chinese Patients With Treacher Collins Syndrome

2021 ◽  
pp. 105566562110375
Author(s):  
Meng Lu ◽  
Bin Yang ◽  
Zixiang Chen ◽  
Haiyue Jiang ◽  
Bo Pan
Keyword(s):  
Rare Variants ◽  
Clinical Care ◽  
Treacher Collins Syndrome ◽  
Chinese Patients ◽  
Pathogenic Variants ◽  
Premature Termination Codons ◽  
Whole Exome ◽  
Exome Aggregation Consortium ◽  
Phenotype Analysis ◽  
Sporadic Cases

Objective The aim of this study was to confirm the pathogenic variants, explore the genotype–phenotype correlation and characteristics of Chinese patients with Treacher Collins syndrome (TCS). Design Clinical details of 3 TCS family cases and 2 sporadic cases were collected and analyzed. Whole-exome sequencing and Sanger sequencing were conducted to detect causative variants. Setting Tertiary clinical care. Patients This study included 8 patients clinically diagnosed with TCS who were from 3 familial cases and 2 sporadic cases. Main Outcome Measures When filtering the database, variants were saved as rare variants if their frequency were less than 0.005 in the 1000 Genomes Project Database, the Exome Aggregation Consortium (ExAC) browser, and the Novogene database, or they would be removed as common ones. The pathogenic variants identified were verified by polymerase chain reaction. The sequencing results were analyzed by Chromas 2.1 software. Results Two novel pathogenic variants (NM_000356.3: c.537del and NM_000356.3: c.1965_1966dupGG) and 2 known pathogenic variants (NM_000356.3: c.1535del, NM_000356.3: c.4131_4135del) were identified within TCOF1 which are predicted to lead to premature termination codons resulting in a truncated protein. There was a known missense SNP (NM_015972.3: c.139G>A) within POLR1D. No phenotype–genotype correlation was observed. Instead, these 8 patients demonstrated the high genotypic and phenotypic heterogeneity of TCS. Conclusions This study expands on the pathogenic gene pool of Chinese patients with TCS. Besides the great variation among patients which is similar to international reports, Chinese patients have their own characteristics in clinical phenotype and pathogenesis mutations.

SMITH-LEMLI-OPITZ SYNDROME WITH CARDIOVASCULAR ABNORMALITY

PEDIATRICS ◽  
1971 ◽  
Vol 47 (5) ◽  
pp. 844-847
Author(s):  
Carl D. Robinson ◽  
Lowell W. Perry ◽  
Amnat Barlee ◽  
Gordon W. Mella
Keyword(s):  
Congenital Heart Disease ◽  
Mental Retardation ◽  
Heart Disease ◽  
Congenital Heart ◽  
Failure To Thrive ◽  
Neuromuscular System ◽  
Cardiac Lesion ◽  
Cardiovascular Abnormality ◽  
Opitz Syndrome ◽  
Unrelated Male

Smith, Lemli, and Opitz in 1964 described in three unrelated male children a syndrome consisting of failure to thrive, mental retardation, microcephaly, disorders of the neuromuscular system, typical facies with anteverted nares, micrognathia, broad maxillary ridge, and low set ears. Over 95% of males with the syndrome have hypospadias with or without cryptorchidism. Females have normal genitalia. Cutaneous syndactyly of the second and third toes commonly occurs. Chromosome karyotype is normal. The present case represents the fortieth to be reported. Of the 40 reported cases, eight or 20% had congenital heart disease which would appear to be emerging as a common feature of the syndrome. No specific cardiac lesion is predominantly seen.

SMAD3 pathogenic variants: risk for thoracic aortic disease and associated complications from the Montalcino Aortic Consortium

2019 ◽  
Vol 56 (4) ◽  
pp. 252-260 ◽  
Author(s):  
Ellen M Hostetler ◽  
Ellen S Regalado ◽  
Dong-Chuan Guo ◽  
Nadine Hanna ◽  
Pauline Arnaud ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Cumulative Risk ◽  
Aortic Disease ◽  
Aortic Aneurysms ◽  
Thoracic Aortic Disease ◽  
Thoracic Aortic Aneurysms ◽  
Missense Variants ◽  
Variant Type ◽  
Pathogenic Variants ◽  
Reduced Penetrance

BackgroundPathogenic variants in SMAD3 cause thoracic aortic aneurysms and dissections, along with aneurysms and rupture of other arteries. Here, we examined differences in clinical presentation of aortic events (dissection or surgical repair of an aneurysm) with respect to age and variant type in an international cohort of individuals with SMAD3 variants.MethodsAortic status and events, vital status and clinical features were abstracted through retrospective review of medical records of 212 individuals with 51 unique SMAD3 variants, including haploinsufficiency (HI) and missense substitutions in the MH2 domain, as well as novel in-frame deletions and missense variants in the MH1 domain.ResultsAortic events were documented in 37% of cases, with dissections accounting for 70% of events. The median age at first aortic event was significantly lower in individuals with SMAD3 MH2 missense variants than those with HI variants (42years vs 49 years; p=0.003), but there was no difference in frequency of aortic events by variant type. The cumulative risk of an aortic event was 50% at 54 years of age. No aortic events in childhood were observed.ConclusionsSMAD3 pathogenic variants cause thoracic aortic aneurysms and dissections in the majority of individuals with variable age of onset and reduced penetrance. Of the covariates examined, the type of underlying SMAD3 variant was responsible for some of this variation. Later onset of aortic events and the absence of aortic events in children associated with SMAD3 variants support gene-specific management of this disorder.

scholarly journals Fetal Anomalies Associated with Novel Pathogenic Variants in TMEM94

Genes ◽  
2020 ◽  
Vol 11 (9) ◽  
pp. 967
Author(s):  
Mohamed H. Al-Hamed ◽  
Nada Alsahan ◽  
Maha Tulbah ◽  
Wesam Kurdi ◽  
Wafa’a I. Ali ◽  
...  
Keyword(s):  
Developmental Disorder ◽  
Chromosomal Microarray ◽  
Global Developmental Delay ◽  
Facial Features ◽  
Chromosomal Microarray Analysis ◽  
Speech Delay ◽  
Loss Of Function ◽  
Pathogenic Variants ◽  
Antenatal Sonography ◽  
First Time

Background: Intellectual developmental disorder with cardiac defects and dysmorphic facies (IDDCDF, MIM 618316) is a newly described disorder. It is characterized by global developmental delay, intellectual disability and speech delay, congenital cardiac malformations, and dysmorphic facial features. Biallelic pathogenic variants of TMEM94 are associated with IDDCDF. Methods and Results: In a prenatal setting, where fetal abnormalities were detected using antenatal sonography, we used trio-exome sequencing (trio-ES) in conjunction with chromosomal microarray analysis (CMA) to identify two novel homozygous loss of function variants in the TMEM94 gene (c.606dupG and c.2729-2A>G) in two unrelated Saudi Arabian families. Conclusions: This study provides confirmation that TMEM94 variants may cause IDDCDF. For the first time we describe the pathogenicity of TMEM94 defects detected during the prenatal period.

Severe in utero under-virilization in a 46,XY patient with Silver-Russell syndrome with 11p15 loss of methylation

2019 ◽  
Vol 32 (2) ◽  
pp. 191-196
Author(s):  
Masanori Adachi ◽  
Maki Fukami ◽  
Masayo Kagami ◽  
Noriko Sho ◽  
Yuichiro Yamazaki ◽  
...  
Keyword(s):  
Failure To Thrive ◽  
Differentially Methylated Region ◽  
Undescended Testes ◽  
Case Presentation ◽  
Body Asymmetry ◽  
Sex Development ◽  
Pathogenic Variants ◽  
Hormone Analog ◽  
Differences Of Sex Development ◽  
Silver Russell Syndrome

Abstract Background Silver-Russell syndrome (SRS) is characterized by growth retardation and variable features including macrocephaly, body asymmetry, and genital manifestations such as cryptorchidism in 46,XY patients. Case presentation The patient was born at 39 weeks with a birth weight of 1344 g. Subtle clitoromegaly warranted a thorough evaluation, which disclosed 46,XY karyotype, bilateral undescended testes, and a rudimentary uterus. Because of severe under-virilization, the patient was assigned as female. Failure to thrive, macrocephaly, and body asymmetry led to the diagnosis of SRS, confirmed by marked hypomethylation of H19/IGF2 intergenic differentially methylated region (IG-DMR). From age 9 years, progressive virilization occurred, which necessitated luteinizing hormone-releasing hormone analog (LHRHa) treatment. Gonadal resection at 15 years revealed immature testes with mostly Sertoli-cell-only tubules. Panel analysis for 46,XY-differences of sex development (DSD) failed to detect any pathogenic variants. Conclusions This is the second reported case of molecularly proven 46,XY SRS accompanied by severe under-virilization. SRS should be included in the differential diagnosis of 46,XY-DSD.

P1785Whole exome sequencing unravels new genes associated with mitral valve prolapse

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A Van Wijngaarden ◽  
Y L Hiemstra ◽  
T T Koopmann ◽  
C A L Ruivenkamp ◽  
E Aten ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Mitral Valve ◽  
Exome Sequencing ◽  
Mitral Valve Prolapse ◽  
Pathogenic Variant ◽  
Pathogenic Variants ◽  
Cardiac Phenotype ◽  
Variant Of Unknown Significance ◽  
Unknown Significance ◽  
Population Databases

Abstract Background Several studies have suggested a familial clustering of mitral valve prolapse (MVP), especially for Barlow disease (BD), which is regarded as the effect of genetic or developmental errors. However, the genetic etiology of MVP, in particular BD, is largely unknown. So far only three genes have been identified: FLNA, DCHS1 and PLD1. Purpose The aim of this study was to identify genes associated with MVP using whole exome sequencing (WES). Methods Patients with MVP, who were classified as BD and/or had a positive family history for MVP, were referred for genetic counseling and WES. In total, 106 unrelated probands were included to identify potentially pathogenic variants in a set of 551 genes associated with cardiovascular development and/or diseases. The population databases Genome Aggregation and WES data from 110 parents of children with mental retardation were used as controls. Variants were analyzed using prediction programs, frequency in the population database and literature search. Variants were divided into the following categories: likely benign, variant of unknown significance or likely pathogenic. Results Thirteen percent (14/106) of the probands had a likely pathogenic variant in seven different genes: DCHS1 (1x), DSP (1x), HCN4 (2x), MYH6 (1x), TMEM67 (1x), TRPS1 (1x) and TTN (7x); the DSP, MYH6 and HCN4 variants cosegregated in affected relatives. None of the 110 parents of children with mental retardation had a likely pathogenic variant in these seven genes. In addition, 31% (33/106) of the probands harbored a variant of unknown significance in 23 different genes, including the genes DSP, FLNA, MYH6 and TTN (Fig). Remarkable, one variant of unknown significance in the FBN2 gene was shared among three unrelated probands and did not occur in population databases. Conclusion WES analysis conducted in probands with MVP using a large panel of genes associated with cardiac development and/or disease confirmed previously known causative genes (DCHS1) and expanded the cardiac phenotype of genes originally associated with cardiomyopathy (DSP, HCN4, MYH6 and TTN). This study is the first study that described the association between MVP and the genes DSP, MYH6 and TTN although the pathogenesis is still unknown. This high yield of likely pathogenic variants emphasizes the importance of genetic screening in MVP patients.

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