Molecular Genetics & Genomic Medicine最新文献

Background: Houge-Janssens syndrome type 2 (HJS2, OMIM 616362) is a rare neurodevelopmental disorder caused by pathogenic variants in PPP2R1A, typically characterized postnatally by hypotonia, developmental delay, intellectual disability, and distinctive craniofacial features.

Methods: We describe a 28-year-old pregnant woman referred for increased nuchal translucency (4.4 mm) and high risk on first trimester screening. Noninvasive prenatal testing showed no common aneuploidies. At 23 weeks of gestation, fetal ultrasound revealed ventriculomegaly and suspected partial agenesis of the corpus callosum. Genetic testing included karyotyping, chromosomal microarray analysis (CMA), and trio-based whole exome sequencing (WES).

Results: Karyotype and CMA were normal. WES identified a de novo heterozygous missense variant in PPP2R1A, NM_014225.6: c.548G>A (p.R183Q), classified as pathogenic. Following genetic counseling, the couple elected to terminate the pregnancy. Integrating our findings with 12 previously reported prenatal cases, we conducted a systematic review of fetal phenotypes associated with PPP2R1A variants. The most common features were ventriculomegaly (92%), agenesis or dysgenesis of the corpus callosum (50%), and congenital heart defects (42%).

Conclusion: We present the most comprehensive synthesis to date of prenatal phenotypes associated with PPP2R1A-related neurodevelopmental disorders. These findings provide crucial insights into the prenatal spectrum of HJS2 and highlight key sonographic indicators to support early diagnosis and genetic counseling.

Background: Distal arthrogryposis with impaired proprioception and touch (DAIPT) is a rare autosomal recessive neurological disease characterized by progressive alteration of mechanosensation. DAIPT is caused by loss of function variants in the PIEZO2 gene that encodes an ionic channel involved in mechanotransduction signaling. Our study started from the case of an 11-year-old boy with skeletal and neuromuscular features suggestive of DAIPT.

Methods: Exome sequencing was performed on the trio. The identified variants in PIEZO2 were validated by Sanger sequencing. Functional assays of the variants were performed by minigene assay in HEK-293 cells and on patient-derived cells using NMD inhibitors.

Results: Trio exome sequencing revealed the presence of two novel variants in the PIEZO2 gene: a nonsense variant (c.1924G>T; p.Glu642*) and an intronic variant of uncertain significance (c.2170-15A>G). Functional analysis demonstrated that the intronic variant disrupts splicing, leading to premature stop codon formation and possible mRNA targeting to nonsense-mediated mRNA decay (NMD). Molecular study in patient-derived fibroblasts with specific NMD inhibitors shows that transcripts derived from both alleles are degraded by NMD, thus confirming the effect of the nonsense variant and enabling reclassification of the VUS.

Conclusion: We present the phenotypic and genetic description of a patient with features suggestive of DAIPT carrying novel biallelic variants in PIEZO2, one of which could be reclassified as pathogenic after functional assays. This study also provides a detailed review of all the published patients with DAIPT and expands the phenotypic and genetic understanding of DAIPT, aiding in diagnosis, genetic counseling, and clinical management.

Background: Latest research on ankylosing spondylitis (AS) indicates a link between the B3GNT2, PSMG1 genes and susceptibility to AS among western populations. However, the association of these three genes with AS in eastern populations remains insufficiently explored. It is necessary to replicate these studies in other populations. Consequently, we chose tagSNPs in these three genes in the Chinese Han population to be sequenced.

Purpose: We tried to find the SNP loci that are associated in both eastern and western populations through repeated experiments. Furthermore, our research extended to examining the link between these genes and the severity of AS. This study aimed to evaluate the association between the tagSNPs of B3GNT2 (rs10865331, rs6545925, rs467250), the rs4676410 SNP on GPR35, and the rs4816648 SNP of PSMG1 with AS susceptibility and disease activity in a Chinese Han population.

Method: We collected blood samples from 497 patients with AS and 498 control subjects and sequenced 5 tagSNPs in B3GNT2, 1 tagSNP in GPR35, and 6 tagSNPs in PSMG1.

Result: Within the five selected tagSNPs of B3GNT2, the rs10865331, rs6545925, and rs4672501 tagSNPs are associated with susceptibility to AS. Additionally, the rs4672501 SNP is not only associated with susceptibility to AS, but also with the severity of AS. For the first time, we find that the rs4676410 SNP on the GPR35 gene is associated with susceptibility to AS, but not associated with the severity of AS in the Chinese Han population. We find for the first time that the rs4816648 SNP of the PSMG1 gene is associated with both susceptibility and severity of ankylosing spondylitis.

Conclusion: B3GNT2 and PSMG1 genes are related to both susceptibility and severity of AS. The GPR35 gene is related to susceptibility to AS in the Chinese Han population, which corroborates the findings of research conducted in western populations.

Pediatric cardiomyopathies are rare, heterogeneous, and challenging conditions, often with a genetic etiology. We estimated the yield of genetic testing in a pediatric cohort with cardiomyopathies and evaluated the potential candidacy to current or emerging treatments based on genetic results. Over one-third had a conclusive genetic test, including 25% of potential candidates for emerging precision therapies or developing pharmacological options.

Background: Very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a rare disorder of long-chain mitochondrial fatty acid oxidation (FAO) caused by biallelic mutations in the acyl-CoA dehydrogenase very-long-chain (ACADVL) gene with autosomal recessive (AR) inheritance. Currently, the ACADVL gene has over 350 VUSs in the ClinVar database that require characterization to determine potential pathogenicity.

Methods: In this study, we performed functional studies and three-dimensional protein structure analysis to identify the pathogenicity of two ACADVL VUSs in a Chinese VLCADD patient with severe clinical symptoms.

Results: Biallelic variants in ACADVL gene c.1055T>C (p.Met352Thr) and c.1269G>A (p.Ser423=) were identified by whole-genome sequencing (WGS) and confirmed using Sanger sequencing. Both variants were recorded in ClinVar database with "conflicting interpretation of its pathogenicity" and need appropriate evidence for reclassification to guide family reproductive planning. Synonymous variant p.Ser423= could result in skipping of exon 12 through mini-gene splicing experiment testing. Further functional studies reveal that both variants yield a mild-to-severe decrease in ACADVL mRNA and protein expression in vitro.

Conclusion: In this study, we determined the pathogenicity of ACADVL variants c.1055T>C (p.Met352Thr) and c.1269G>A (p.Ser423=) via experimental and in silico analysis. The findings contribute to expanding the variant spectrum in the ACADVL gene, and exploring the pathogenicity of VUS may provide us with further understanding of the disease.

Background: Most reclassified genetic test results are clinically inactionable and burdensome for healthcare providers to return to patients. The feasibility of using electronic patient portals (e.g., MyChart) to return reclassified results remains unclear.

Methods: Patient and provider initiated MyChart actions were obtained from MyChart data and matched to patient demographic and clinical information using unique patient medical record numbers. Data on who (patient or provider) sent and read these messages and when (date and time) were collected for clinically actionable and inactionable reclassifications.

Results: Among 801 patients with 828 reclassified variants in cancer susceptibility genes, 551 had an active MyChart account at the time of reclassification. Patients with active MyChart accounts were less likely to be Hispanic (p < 0.001) compared to other ethnic groups. Of these, 302 (55%) were notified about 308 reclassified results (307 inactionable and 1 actionable) via MyChart messages, and 80% (244/302) read the message within a median time of 3.6 h.

Conclusion: We find that it is feasible to return reclassified results via electronic patient portals for most patients, but alternative modalities are still necessary. Unidirectional, low-touch modalities of recontact can be used to efficiently return the increasing number of inactionable reclassified results.

Background: Hearing loss, characterized by significant genetic heterogeneity, is a widespread global disorder. Mutations in the OTOG and OTOGL genes have recently been implicated in non-syndromic sensorineural hearing loss. However, the mutation spectrum of OTOGL and its functional relevance remain incompletely understood.

Methods: We investigated a Chinese family with unexplained hearing loss using whole-exome sequencing. Compound heterozygous mutations in the OTOGL gene were identified and validated through Sanger sequencing. The proband's clinical features were assessed through audiological evaluations, and genotype-phenotype correlation analysis was conducted. Additionally, single-cell RNA sequencing analysis of the inner ear was performed to explore OTOGL's expression profile in auditory-related cell types.

Results: Two compound heterozygous mutations in the OTOGL gene (p.Ile34Val and p.Phe319del) were identified in the proband, a 6-year-old boy with moderate congenital hearing loss. These mutations are predicted to be pathogenic and may explain the observed phenotype. Single-cell RNA sequencing revealed specific OTOGL expression in key auditory-related cell types, providing insights into its developmental and functional roles in the inner ear.

Conclusion: The findings have marked implications for molecular diagnosis and genetic counseling, potentially guiding more personalized treatment and intervention strategies in clinical practice.

Introduction: Perlman syndrome is a rare autosomal recessive overgrowth disorder with a predisposition to Wilms tumor, caused by biallelic variants in DIS3L2. The majority of patients die in infancy due to respiratory and/or renal failure, limiting the reports of patients surviving into childhood.

Methods: Exome sequencing was performed in the proband and her older brother. A younger sibling subsequently underwent targeted variant analysis. RNA sequencing was utilized to investigate the functional impact of the missense variant.

Results: Three siblings presented at birth with fetal macrosomia, dysmorphic facial features, and facial hypotonia. The proband had early speech delay and was diagnosed with Wilms tumor at 3 years old. Her brothers both had developmental delay presenting within the first year of life. Genetic testing identified compound heterozygous variants in DIS3L2 (NM_152383.5): c.127C>T (p.Arg43Ter) (paternal)/c.2381G>A (p.Arg794His) (maternal).

Conclusion: Our findings expand the genetic and clinical spectrums associated with Perlman syndrome and increase the understanding of the phenotype observed in childhood. They also support consideration of genetic testing for Perlman syndrome in individuals and sibships with macrosomia, developmental delay, and characteristic facial dysmorphisms, with or without the presence of Wilms tumor.

Background: SOST encodes a secreted glycoprotein that is similar in sequence to the differential screening-selected gene aberrative in neuroblastoma (DAN) family of bone morphogenetic protein (BMP) antagonists. Pathogenic variants in the SOST gene result in sclerosteosis, van Buchem disease (VBD), or craniodiaphyseal dysplasia. SOST-related genetic disorders are very rare, and limited studies have reported variants associated with sclerosteosis.

Methods: Clinical tests such as magnetic resonance imaging (MRI), computed tomography (CT), emission computed tomography (ECT), electromyogram (EMG), routine blood tests, and physical examinations were conducted for the proband. Trio-whole exome sequencing (Trio-WES) was performed, and the rare variants (allele frequency < 0.01) in the exon and splicing regions were selected for further pathogenic evaluation. Candidate pathogenic variants were validated through Sanger sequencing. The wild and mutant SOST sequences were cloned into the pcDNA3.1 expression vector, and the RNA and protein expression levels were investigated in the HEK293T cell line.

Results: In this study, we present a case study of a proband who displays abnormal facial expressions accompanied by numbness. The results of the brain MRI show thickening of the skull and disappearance of the diplopia signal. The temporal bone CT scan indicates diffuse osteosclerosis affecting the bilateral ossicular chains and internal auditory meatus, as well as stenosis of the bilateral internal auditory meatus. Trio-WES sequencing detected a novel homozygous variant in the proband: NM_025237.3(SOST): c.327C>A (p.Cys109*), which was also validated in his sister from the same family. According to the ACMG guidelines, the variant is classified as "likely pathogenic." The in vitro experiments demonstrated that the variant caused a decrease in SOST expression at RNA and protein level and produced a truncated protein.

Conclusion: The report presents new evidence for the clinical diagnosis of SOST-related facial numbness and expands the variant spectrum of SOST.