Targeted sequencing identifies a novel SH2D1A pathogenic variant in a Chinese family: Carrier screening and prenatal genetic testing

Abstract

X-linked lymphoproliferative disease type 1 (XLP1) is a rare primary immunodeficiency characterized by a clinical triad consisting of severe EBV-induced hemophagocytic lymphohistiocytosis, B-cell lymphoma, and dysgammaglobulinemia. Mutations in SH2D1A gene have been revealed as the cause of XLP1. In this study, a pregnant woman with recurrence history of birthing immunodeficiency was screened for pathogenic variant because the proband sample was unavailable. We aimed to clarify the genetic diagnosis and provide prenatal testing for the family. Next-generation sequencing (NGS)-based multigene panel was used in carrier screening of the pregnant woman. Variants of immunodeficiency related genes were analyzed and prioritized. Candidate variant was verified by using Sanger sequencing. The possible influence of the identified variant was evaluated through RNA assay. Amniocentesis, karyotyping, and Sanger sequencing were performed for prenatal testing. We identified a novel de novo frameshift SH2D1A pathogenic variant (c.251_255delTTTCA) in the pregnant carrier. Peripheral blood RNA assay indicated that the mutant transcript could escape nonsense-mediated mRNA decay (NMD) and might encode a C-terminal truncated protein. Information of the variant led to success prenatal diagnosis of the fetus. In conclusion, our study clarified the genetic diagnosis and altered disease prevention for a pregnant carrier of XLP1.

Aberrant splicing caused by a novel KMT2A variant in Wiedemann–Steiner syndrome

“…However, our RNA analysis revealed approximately equal levels of mutant and wild‐type transcripts, indicating an escape from NMD. This phenomenon aligns with previous studies that have shown NMD escape can occur for some PTC‐introducing variants predicted to undergo NMD (Zhang et al., 2017). The abnormal transcript escaping NMD may produce a truncated protein product lacking functionally critical domains.…”

A rare cardiac phenotype of dextrocardia observed in a fetus with 1p36 deletion syndrome and a balanced translocation: a prenatal case report

“…The amniocentesis was performed to obtain the fetal samples after signing the informed consent as described previously [ 5 ]. Amniotic fluid cells were cultured according to the standard protocol in two independent flasks.…”

Targeted Sequencing and RNA Assay Reveal a Noncanonical JAG1 Splicing Variant Causing Alagille Syndrome

“…A 2,181-gene medical exome panel was used for exomes and flanking sequence capture. The procedure for preparation of library was published previously (Liu et al, 2015;Zhang et al, 2017). Sequencing of the captured target regions was performed paired-end sequencing (2×90bp) on Illumina HiSeq2500 Analyzer (Illumina, San Diego, CA, USA).…”

“…Variant calling and annotation were performed using the Genome Analysis Toolkit (GATK; version 3.5) and ANNOtate VARiation (ANNOVAR) (Yang and Wang, 2015), respectively. The resulting variants were prioritized with our in-house developed pipeline (MultiOmics One) (Zhang et al, 2017). The interpretation of variants was based on the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guideline (Richards et al, 2015).…”