Jun 2026· Journal of Medical Genetics· Vol 63, pp. 605 - 612· 0 citations· 46 references
Medicine
TL;DR
The data suggest PREP deficiency as the underlying cause of a syndromic neurodevelopmental disorder.
Abstract
Background Neurodevelopmental disorders are one of the most prevalent reasons for genetic testing in childhood. Despite the identification of over 1950 associated genes, many proposed candidate genes lack convincing gene-disease validity. The gene PREP encodes the broadly expressed prolyl endopeptidase whose exact function remains largely unknown. A homozygous PREP variant has been reported once as a candidate gene in two siblings with intellectual disability but no functional studies were conducted. Methods Exome and trio genome sequencing were performed in two unrelated families as part of larger cohorts. Segregation analysis, RNA sequencing and immunoblots were performed to further examine the pathogenicity of detected PREP variants. Results We report three individuals from two unrelated families who presented with intellectual disability, behavioural abnormalities, strabismus, generalised muscular hypotonia, dysmorphic facial features and epilepsy. Exome and genome sequencing identified two different homozygous rare PREP variants: c.1570_1573dup, p.(Asn525Thrfs*5) and c.1839-2A>G, p.?. RNA sequencing confirmed the detected intronic variant to result in two aberrant mRNA isoforms. In patient-derived cells immunoblots showed absence of PREP protein. Conclusion Our data suggest PREP deficiency as the underlying cause of a syndromic neurodevelopmental disorder.
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.
Jingjing Zhang, Jing He, H. Pan et al.· European Journal of Medical...· 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
This study expands the clinical, genetic, and molecular spectrum of EZH1-associated neurodevelopmental disorders by demonstrating that reduced EZH1 expression is consistent with a loss-of-function disease mechanism.
Mohamed Baity, Khalid K Alharbi, Eman Alobeid et al.· International Journal of Mol...· 0 citations
Intellectual disability (ID) affects approximately 1%–3% of the population and spans diverse clinical presentations with marked genetic heterogeneity, especially in consanguineous populations where autosomal‐recessive ID is common. Despite advances in diagnostic methods, ~50% of individuals with ID remain without a molecular diagnosis. Genome sequencing (GS) can detect variant classes poorly captured by other methodologies, including deep intronic splice changes and structural variants. We performed short‐read GS on 38 Iranian autosomal recessive intellectual disability (ARID) families that remained unsolved after exome sequencing (ES) and two phases of reanalysis. Sequencing and variant calling were performed on DRAGEN Bio‐IT Platform with GRCh38 and variants were annotated in Golden helix Varseq software and the AnnotSV tool. GS yielded diagnoses in 2 of 38 families (5.3%), identifying a homozygous deep‐intronic ATP8A2 variant (c.1473 + 519C > T) that creates a cryptic donor site and a 57‐bp pseudoexon, and a homozygous ~103‐kb CNTNAP2 deletion removing the in‐frame Exon 2. Additionally, GS uncovered a homozygous NCOR1 missense variant that represents a novel candidate gene for ARID, but further studies are required to confirm the gene–disease association. The ATP8A2 and CNTNAP2 variants were uniquely detectable by GS. In conclusion, in a challenging, ES‐negative ARID cohort, GS provided an additional ~5.3% diagnostic yield by uncovering a noncoding splice alteration and a large intragenic deletion. These results underscore GS as a valuable, though still modest, tool over ES and highlight significant interpretation challenges in noncoding regions. Continued advances in functional assays and complementary long‐read technologies will be essential to further reduce the diagnostic gap in unresolved ID.
Ebrahim Shokouhian, Masoumeh Moslemi, Masoumeh Goleyjani Moghadam et al.· Human Mutation· 0 citations
Consanguinity increases the risk of autosomal recessive disorders and may result in the co-segregation of multiple pathogenic variants within the same family. Although most affected families are explained by a single genetic diagnosis, multilocus pathogenic variation can produce complex and overlapping clinical phenotypes. We investigated a consanguineous Pakistani family with three affected siblings, including dizygotic twins presenting with neurodevelopmental disorder and hearing loss, using detailed clinical evaluation, long-read whole-genome sequencing, bulk transcriptomics, protein profiling, and segregation analysis to determine the underlying molecular diagnoses. One sibling presented with isolated non-syndromic hearing loss, whereas the dizygotic twins exhibited severe neurodevelopmental impairment characterized by global developmental delay, spastic quadriplegic cerebral palsy, microcephaly, and white matter abnormalities. Long-read whole-genome sequencing identified a homozygous start-loss variant in HPDL (c.3G>C) in both twins, consistent with HPDL-related neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA). In addition, a novel homozygous nonsense variant in EPS8 (c.1294C>T) was identified in one twin and the sibling with isolated hearing loss, explaining the auditory phenotype. Long-read transcriptomic analysis demonstrated absence of detectable EPS8 transcripts in both individuals homozygous for the nonsense variant, providing transcript-level evidence consistent with a loss-of-function mechanism. Genome-wide comprehensive proteomic profiling (SomaScan) identified distinct protein abundance profiles across family members, with the most pronounced alterations observed in the twins affected by HPDL-related neurodevelopmental disease, particularly the individual harboring pathogenic variants in both EPS8 and HPDL. This study expands the mutational spectrum of EPS8 and highlights the independent segregation of two autosomal recessive disorders within the complex consanguineous family, resulting in distinct and blended phenotypes.
Bassam Jamalalail, Ahmed A. Khalifa, Bipin Balan et al.· bioRxiv· 0 citations
This is the second report of autosomal recessive epilepsy associated with biallelic CACNB4 variants and genetic investigations play a crucial role in identifying mutation hotspots, facilitating more accurate diagnoses and enhancing the design of diagnostic panels for early detection.