scholarly journals Correction to: Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics (ACMG)

2021 ◽  
Author(s):  
Anthony R. Gregg ◽  
Mahmoud Aarabi ◽  
Susan Klugman ◽  
Natalia T. Leach ◽  
Michael T. Bashford ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Medical Genetics ◽  
Genetics And Genomics

Biochemical and genetic characterization of 16 patients with propionic acidemia

2021 ◽  
pp. 3-14
Author(s):  
А.С. Галушкин ◽  
Е.Ю. Пыркова ◽  
М.В. Куркина ◽  
С.В. Михайлова ◽  
В.П. Воронцова ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
3D Model ◽  
Genetic Characterization ◽  
Propionic Acidemia ◽  
Medical Genetics ◽  
Organic Acidemia ◽  
Biochemical Tests ◽  
Genetics And Genomics ◽  
Hydroxypropionic Acid

Пропионовая ацидемия (ПА) - редкое наследственное заболевание с аутосомно-рецессивным типом наследования, относится к «классическим», т.е. наиболее часто диагностируемым органическим ацидемиям. В данной работе представлена биохимическая и молекулярно-генетическая характеристика 16 пациентов с ПА, выявленных в Российской Федерации. У большинства обследованных пациентов первые симптомы проявились в первые месяцы жизни, наиболее частые из них: нарушения вскармливания, судороги, мышечная гипотония, угнетение сознания. При биохимическом исследовании (ГХ-МС и МС/МС) у пациентов было выявлено повышение концентрации 3-гидроксипропионой кислоты, метилцитрата, пропионилглицина, C3, глицина, которые являются патогномоничными маркерами этой патологии. В результате молекулярно-генетического анализа в генах PCCA и PCCB было выявлено 6 неописанных ранее вариантов нуклеотидной последовательности (4 варианта в гене PCCA, 2 - в гене PCCB), один из которых (PCCB: c.655-2A>G) имеет высокую частоту (17,2%, 5/29 мутантных аллелей генов PCCA и PCCB) в исследуемой выборке. Локализация миссенс-вариантов и их влияние на структуру белка были продемонстрированы на 3D-модели фермента пропионил-КоА-карбоксилазы. Выявленным вариантам были присвоены критерии патогенности в соответствии с рекомендациями American College of Medical Genetics and Genomics (ACMG). Propionic acidemia is a rare autosomal recessive metabolic disorder, characterized as classic organic acidemia. The article represents biochemical and molecular characterization of 16 patients diagnosed with propionic acidemia in Russia. Symptoms appeared during the first months after birth in most cases. Poor feeding, seizures, hypotonia, lethargy were the most frequent symptoms. Biochemical tests (GC-MS and MS/MS) showed elevated 3-hydroxypropionic acid, methylcitrate, propionylglycine, C3 in patients blood. Six undescribed earlier variants were found as a result of PCCA & PCCB (4 variants - PCCA, 2 - PCCB) genes DNA-tests. Variant c.655-2A>G in PCCB is the most frequent in this group (17.2%). Localization of missense variants and their effect on protein was demonstrated using propionyl-CoA carboxylase 3D model. New variants were classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines.

scholarly journals The global carrier frequency and genetic prevalence of Upshaw-Schulman syndrome

2021 ◽  
Author(s):  
Ting Zhao ◽  
Shanghua Fan ◽  
Liu Sun
Keyword(s):  
Data Mining ◽  
Allele Frequency ◽  
Thrombotic Microangiopathy ◽  
Carrier Frequency ◽  
Autosomal Recessive ◽  
Autosomal Recessive Disease ◽  
Medical Genetics ◽  
Allele Frequencies ◽  
Pathogenic Variants ◽  
Genetics And Genomics

Purpose: Upshaw-Schulman syndrome (USS) is an autosomal recessive disease of thrombotic microangiopathy, caused by pathogenic variants in ADAMTS13. We aimed to (1) perform data mining pathogenicity of ADAMTS13 variants, (2) estimate carrier frequency and genetic prevalence of USS from gnomAD data, and (3) curated ADAMTS13 gene pathogenic variants database. Methods: PubMed and Scopus were comprehensive retrieved. All previously reported pathogenic ADAMTS13 variants were compiled and annotated with gnomAD allele frequencies. Pooled global and population-specific carrier frequency and genetic prevalence for USS were calculated using Hardy-Weinberg equation. Results: we mined reported disease-causing variants, of these were present in gnomAD exomes v2.1.1, filtering by allele frequency, pathogenicity of variants were classified by American College of Medical Genetics and Genomics criteria. The genetic prevalence and carrier frequency of USS was 0.43 per 1 million (95% CI: [0.36, 0.55]) and 1.31 per thousand, respectively. Combining known with novel pathogenic/likely pathogenic variants, the genetic prevalence and carrier frequency are 1 per 1 million (95% CI: [0.89, 1.37]) and 2.1 per thousand, respectively. Conclusion: the genetic prevalence and carrier frequency of Upshaw-Schulman syndrome are within range of previously rough estimated.

scholarly journals The global carrier frequency and genetic prevalence of Upshaw-Schulman syndrome

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Ting Zhao ◽  
Shanghua Fan ◽  
Liu Sun
Keyword(s):  
Allele Frequency ◽  
Carrier Frequency ◽  
Autosomal Recessive ◽  
Autosomal Recessive Disease ◽  
Medical Genetics ◽  
Allele Frequencies ◽  
The Novel ◽  
Thrombotic Microangiopathies ◽  
Pathogenic Variants ◽  
Genetics And Genomics

Abstract Background Upshaw–Schulman syndrome (USS) is an autosomal recessive disease characterized by thrombotic microangiopathies caused by pathogenic variants in ADAMTS13. We aimed to (1) curate the ADAMTS13 gene pathogenic variant dataset and (2) estimate the carrier frequency and genetic prevalence of USS using Genome Aggregation Database (gnomAD) data. Methods Studies were comprehensively retrieved. All previously reported pathogenic ADAMTS13 variants were compiled and annotated with gnomAD allele frequencies. The pooled global and population-specific carrier frequencies and genetic prevalence of USS were calculated using the Hardy-Weinberg equation. Results We mined reported disease-causing variants that were present in the gnomAD v2.1.1, filtered by allele frequency. The pathogenicity of variants was classified according to the American College of Medical Genetics and Genomics criteria. The genetic prevalence and carrier frequency of USS were 0.43 per 1 million (95% CI: [0.36, 0.55]) and 1.31 per 1 thousand population, respectively. When the novel pathogenic/likely pathogenic variants were included, the genetic prevalence and carrier frequency were 1.1 per 1 million (95% CI: [0.89, 1.37]) and 2.1 per 1 thousand population, respectively. Conclusions The genetic prevalence and carrier frequency of USS were within the ranges of previous estimates.

Kindler's Syndrome with Recurrent Neutropenia: Report of Two Cases from Saudi Arabia

2020 ◽  
Author(s):  
Yousef Binamer ◽  
Muzamil A. Chisti
Keyword(s):  
Autosomal Recessive ◽  
Common Mechanism ◽  
Sequencing Analysis ◽  
Loss Of Function ◽  
Skin Atrophy ◽  
Whole Exome ◽  
Infancy And Childhood ◽  
Genetics And Genomics ◽  
New Feature ◽  
Generation Sequencing

AbstractKindler syndrome (KS) is a rare photosensitivity disorder with autosomal recessive mode of inheritance. It is characterized by acral blistering in infancy and childhood, progressive poikiloderma, skin atrophy, abnormal photosensitivity, and gingival fragility. Besides these major features, many minor presentations have also been reported in the literature. We are reporting two cases with atypical features of the syndrome and a new feature of recurrent neutropenia. Whole exome sequencing analysis was done using next-generation sequencing which detected a homozygous loss-of-function (LOF) variant of FERMT1 in both patients. The variant is classified as a pathogenic variant as per the American College of Medical Genetics and Genomics guidelines. Homozygous LOF variants of FERMT1 are a common mechanism of KS and as such confirm the diagnosis of KS in our patients even though the presentation was atypical.

scholarly journals Diagnostic exome-based preconception carrier testing in consanguineous couples: results from the first 100 couples in clinical practice

2021 ◽  
Author(s):  
Suzanne C. E. H. Sallevelt ◽  
Alexander P. A. Stegmann ◽  
Bart de Koning ◽  
Crool Velter ◽  
Anja Steyls ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Rare Variants ◽  
Clinical Care ◽  
Carrier Testing ◽  
Carrier Status ◽  
Routine Diagnostics ◽  
Affected Offspring ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
Genetics And Genomics

Abstract Purpose Consanguineous couples are at increased risk of being heterozygous for the same autosomal recessive (AR) disorder(s), with a 25% risk of affected offspring as a consequence. Until recently, comprehensive preconception carrier testing (PCT) for AR disorders was unavailable in routine diagnostics. Here we developed and implemented such a test in routine clinical care. Methods We performed exome sequencing (ES) for 100 consanguineous couples. For each couple, rare variants that could give rise to biallelic variants in offspring were selected. These variants were subsequently filtered against a gene panel consisting of ~2,000 genes associated with known AR disorders (OMIM-based). Remaining variants were classified according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines, after which only likely pathogenic and pathogenic (class IV/V) variants, present in both partners, were reported. Results In 28 of 100 tested consanguineous couples (28%), likely pathogenic and pathogenic variants not previously known in the couple or their family were reported conferring 25% risk of affected offspring. Conclusion ES-based PCT provides a powerful diagnostic tool to identify AR disease carrier status in consanguineous couples. Outcomes provided significant reproductive choices for a higher proportion of these couples than previous tests.

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