Jul 2026· European Journal of Medical Genetics· Vol 83, pp.
105097
· 0 citations· 22 references
Medicine
TL;DR
This study expands the pathogenic variant spectrum of HUWE1 and provides novel molecular evidence for the clinical diagnosis of Turner-type XLID and is of significant value for genetic counseling, carrier screening, and prenatal diagnosis for the affected families.
Abstract
Objective
To characterize the clinical phenotypes and identify the genetic etiology in four unrelated families affected by Turner-type X-linked intellectual disability (XLID).
Methods
Peripheral blood samples were collected from four probands and their parents. Genomic DNA was extracted, and a comprehensive genetic analysis was performed using trio-based Whole Exome Sequencing (WES) combined with low-pass Copy Number Variation sequencing (CNV-seq). Candidate variants were subsequently validated via Sanger sequencing.
Results
Genetic analysis identified distinct variants in the HUWE1 across the four families. Specifically, a hemizygous c.10034A>T (p.Lys3345Met) variant was identified in the proband of Family 1; a heterozygous c.9209G>A (p.Arg3070His) variant in Family 2; a heterozygous c.12688T>C (p.Phe4230Leu) variant in Family 3; and a hemizygous c.9070G>A (p.Ala3024Thr) variant in Family 4. According to the ACMG guidelines, all four variants were classified as "Likely Pathogenic" based on the following criteria: PS2 + PM2_Supporting + PP2 + PP3. Notably, the c.10034A>T (p.Lys3345Met), c.12688T>C (p.Phe4230Leu), and c.9070G>A (p.Ala3024Thr) are novel variants that have not been previously reported. All probands were clinically diagnosed with Turner-type XLID.
Conclusions
This study expands the pathogenic variant spectrum of HUWE1 and provides novel molecular evidence for the clinical diagnosis of Turner-type XLID. These findings are of significant value for genetic counseling, carrier screening, and prenatal diagnosis for the affected families.
It is demonstrated that even in the absence of functional experiments, comprehensive family analysis can provide crucial clues for variant of uncertain significance (VUS) interpretation.
Xiulan Hao, Yanchou Ye, Man Liu et al.· Frontiers in Genetics· 0 citations
The co-occurrence of variants in AKAP4 and RNF220 may suggest an oligogenic etiology of NOA and contribute to the phenotypic variability associated with AKAP4 variants.
Razieh Ebrahimi Askari, A. Malcher, Fateme Sefid et al.· International Journal of Mol...· 0 citations
Purpose Hereditary hearing loss is a genetically heterogeneous disorder, with more than 120 genes implicated in the non-syndromic forms. The genetic cause of non-syndromic hearing loss (NSHL) in a Chinese Han family was investigated, and the function of the identified mutation was characterized. Methods The family members were clinically evaluated. Targeted next-generation sequencing of 414 deafness-related genes was performed on the proband. The identified variants were validated in the family members of the proband using Sanger sequencing and PCR. The functional impacts of the variants on splicing were predicted using SpliceAI and MaxEntScan. Results Two compound heterozygous CDH23 mutations (c.7054+1G>A and c.4209+794_4825 del) were identified in a thirteen-month-old girl with NSHL. Sanger sequencing confirmed recessive inheritance, with each unaffected parent carrying a single heterozygous variant. The c.7054+1G>A variant is a canonical splice donor variant predicted to severely disrupt splicing (SpliceAI donor loss score: 0.99; MaxEntScan score reduced from 10.28 in the wild-type to 2.10 in the mutant, a 79.57% reduction). The c.4209+794_4825 del is a 6.45 kb heterozygous deletion encompassing exons 35–38, predicted to resulted in the in-frame skipping of exons 35–38. AlphaFold-based structural modeling revealed marked conformational changes in the mutant extracellular domain, supporting the hypothesis that these variants compromised CDH23-mediated tip-link formation and mechanotransduction. Conclusion We identified two novel compound heterozygous CDH23 mutations (c.7054+1G>A and c.4209+794_4825 del) in a Chinese Han family, expanding the known spectrum of CDH23 mutation and adding to the understanding of the genotype–phenotype correlations in NSHL.
Pengcheng Xu, Qi Liao, Yun Lin et al.· International Journal of Gen...· 0 citations
Objective: The objective of this study was to analyze the clinical phenotypes and genetic variant characteristics of four unrelated Chinese children carrying pathogenic variants in the CTCF gene and to explore the genotype–phenotype heterogeneity of autosomal dominant intellectual disability type 21 (MRD21, OMIM 615,502). Methods: Four pediatric patients admitted to Beijing Children’s Hospital, Capital Medical University, from 2020 to 2024 were enrolled in this retrospective study. All patients underwent medical history collection, physical examination, laboratory tests and high-throughput sequencing. Identified variants were verified in the probands and parents via Sanger sequencing or CNV-seq. Results: Four distinct heterozygous CTCF variants were identified: a missense variant c.1117C>T (p.His373Tyr); an 8.92 Mb microdeletion at 16q21-q22.1 (arr[GRCh37] 16q21q22.1(58,986,875–67,907,636)×1), encompassing the entire CTCF gene; a frameshift deletion c.615_618delGAAA (p.Lys206Profs*15); and an intragenic deletion of exons 8–10. Parental testing confirmed that all identified variants were of de novo origin. The missense variant and the frameshift deletion have been reported previously in ClinVar (VCV000521287.19 and VCV001308122.2), but the two deletions were not found in public databases. Three patients presented with global developmental delay consistent with MRD21, with variable additional features including autistic-like behavior and facial dysmorphism. Notably, two of these patients showed somatic overgrowth with height and weight above the 97th percentile, contrasting with the short stature classically emphasized in MRD21. The fourth patient was a preterm infant with neonatal chylothorax, cardiopulmonary failure, and multiple congenital cardiovascular malformations; developmental assessment at a corrected age of 11 months showed only mild lags. Conclusions: This study expands the spectrum of pathogenic CTCF variants in the Chinese population and underscores the marked phenotypic heterogeneity of CTCF-related disorders, ranging from benign developmental outcomes with complete catch-up to severe neonatal multisystem involvement. In neonates presenting with unexplained chylothorax and multisystem abnormalities, especially when accompanied by features suggestive of a neurodevelopmental syndrome, CTCF should be considered in the differential diagnosis. Given this heterogeneity, a broad genomic approach rather than targeted CTCF screening is recommended in patients with complex presentations.
Juan Du, Muhan Li, Aimin Liang et al.· Genes· 0 citations
Objective Stickler syndrome (SS) is a genetically and clinically heterogeneous connective tissue disorder. This study aimed to investigate the genetic etiology in a Chinese patient associated with SS and characterize the novel pathogenic variant. Methods Whole-exome sequencing (WES) was performed on the proband, and Sanger sequencing was conducted on both the proband and all available family members for variant validation. Variants were filtered by multiple in silico tools and co-segregation analysis based on American College of Medical Genetics and Genomics (ACMG) Guidelines. Structural consequences were evaluated via molecular dynamics (MD) simulations. A systematic review was conducted to summarize the genotypic and phenotypic features of previously reported LOXL3-related SS and early-onset high myopia (eoHM) cases, including four published case reports of independent SS pedigrees and two studies on eoHM. Results A novel compound heterozygous LOXL3 mutation (NM_032603.5:c.1348T>A(p.Trp450Arg); NM_032603.5:c.824dup(p.Ala277Cysfs*57)) was identified in a 5-year-old female child diagnosed with SS, who exhibited eoHM, vitreous syneresis, cleft palate, foveal hypoplasia (FVH), and mild craniofacial dysmorphism. In silico analysis using Variant Effect Predictor (VEP) predicted both variants as deleterious. Molecular dynamics (MD) simulations revealed that the novel NM_032603.5:c.1348T>A(p.Trp450Arg) mutation significantly destabilizes LOXL3 protein structure. Specifically, this variant increases structural flexibility and solvent accessibility while reducing hydrogen bond formation, resulting in a disordered protein conformation. Furthermore, p.Trp450Arg perturbs the copper-binding pocket and impairs copper ion coordination. Both variants co-segregated with clinical phenotypes in the family. Collectively, these functional and genetic findings, combined with clinical evidence, support the two variants as likely pathogenic and pathogenic respectively following the ACMG guidelines. The literature review revealed that high myopia is the most frequent clinical feature of LOXL3-related disorders, followed by FVH. Conclusion Compound heterozygous LOXL3 variants are associated with the SS phenotype. This study broadens the recessive mutational and phenotypic spectrum of LOXL3-related SS, supports refined disease subclassification and also aids genetic testing and clinical diagnosis of this disorder. It underscores the critical role of the Trp450 residue in maintaining protein structural stability and provides atomic-level insights into the molecular pathogenesis of this disorder.
Min Ye, Shuai Li, Rui Li et al.· Frontiers in Genetics· 0 citations
BACKGROUND
Sensorineural hearing impairment (SNHI) is a common disorder with a significant genetic basis. Standard next-generation sequencing (NGS) often fails to accurately identify pathogenic variants in the STRC gene due to its complex genomic structure, including large rearrangements and a highly homologous pseudogene. Long-read sequencing (LRS) offers improved resolution for these complex regions.
METHODS
We developed a comprehensive workflow that integrates PacBio-based LRS with marker-mediated refinements and MLPA validations to specifically address pseudogene interference. This methodology was applied to analyze the STRC gene in a cohort of 100 unrelated Taiwanese patients with SNHI of unknown genetic origin after initial NGS screening.
RESULTS
We identified bi-allelic STRC variants in 11 unrelated patients (11% diagnostic yield), including homozygous deletions, compound heterozygous deletions and conversions, and compound heterozygous single nucleotide variants (SNVs) and copy number variants (CNVs). All unrelated cases resolved with bi-allelic STRC variants were affected with mild or moderate SNHI, occupying 15.1% of total 73 mild-to-moderate SNHI patients in this study.
CONCLUSION
Our results highlight the diagnostic utility of this combined strategy, integrating LRS with marker-mediated refinements that validated by MLPA assays, in detecting complex STRC variants and advance the understanding of the genetic etiology of SNHI that remains unresolved by conventional NGS approaches.
