Jul 2026· Exploration of Neuroprotective Therapy· 0 citations· 45 references
Abstract
Aim: Identify new genetic variants linked to neurodevelopmental disorders to be used in routine genetic diagnostics. Methods: Whole exome sequencing (WES) was used for ten unrelated families from Jordan characterized by one or two affected members with neurodevelopmental disorders (NDDs), in which the parents are consanguineous in nine families. Results: Ten variants are identified in this study; one variant per family. Eight variants are identified by cross-link with the pathogenic variants in ClinVar and in our in-house database, and two variants are identified for the first time. Nine of the total identified variants are homozygous in the nine consanguineous families and one variant is heterozygous in the non-consanguineous family. Three of the identified variants were previously reported in unrelated Jordanian families compared to the families in this study. These three variants are NM_018359.5:c.344T>A;p.Val115Glu in the gene UFSP2, NM_000487.6:c.256C>G;p.Arg86Gly in the gene ARSA and NM_017882.3:c.144G>A;p.Trp48* in the gene CLN6. The variants that are identified for the first time are splicing variants; splice donor variant NM_000433.4:c.366+1G>C in the gene NCF2 and splice acceptor variant NM_000191.3:c.498-1G>A in the gene HMGCL. Conclusions: The results of this study stress the importance of continuous research using WES for NDDs in Jordan to identify new variants.
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
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.
Neurodevelopmental disorders (NDDs) are a group of conditions that impair the development and function of the central nervous system. Recently, variants in the EZH1 gene have been associated with neurodevelopmental disorders. Here, using whole-exome sequencing coupled with confirmatory Sanger sequencing, we identified a homozygous nonsense variant in EZH1 in two affected siblings. Both parents were heterozygous carriers of the variant. The variant is predicted to result in a 44-amino acid C-terminal truncation within the catalytic SET domain, leading to loss of protein function. RT-qPCR analysis revealed significantly reduced EZH1 mRNA expression in patient-derived peripheral blood cells. The index patient (female) also exhibited elevated gamma-glutamyl transferase (GGT) levels and hypoalbuminemia, whereas the affected male presented with central precocious puberty. This study further 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
More than 70% of non-obstructive azoospermia (NOA) cases remain idiopathic, and the underlying genetic causes need to be investigated. In this study, we aimed to identify genes and variants associated with the etiology of NOA. Two NOA patients from consanguineous families, with normal karyotypes and no Y-chromosome microdeletions, were selected for whole-genome sequencing (WGS). Candidate variants were validated by Sanger sequencing. Structural protein modeling and assessment of mutation-induced changes in molecular interactions were performed using SWISS-MODEL and AlphaFold. We identified a candidate homozygous missense variant (c.899C>T, p.(Ser300Phe); rs375931805) in SOX30 in one patient; this transcription factor is highly expressed in the testis. In the second patient, a homozygous missense variant (c.1472C>T, p.(Thr491Met); rs746902232) in RNF220 and a hemizygous missense variant (c.2354A>G, p.(Gln785Arg) in the X-linked AKAP4 gene were simultaneously detected. Previous studies have shown that SOX30 knockout in mice leads to meiosis I arrest and impaired spermiogenesis. AKAP4 is exclusively expressed in the testis, and missense variants have been reported in different forms of male infertility. 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
Background This study aimed to systematically analyze a Chinese family with Kallmann syndrome (KS), evaluate the pathogenicity of a candidate variant through co-segregation analysis and bioinformatic predictions, and provide clinical intervention for the family. Methods This study included a Chinese family with KS comprising 40 members in total (37 living, 3 deceased). Whole-genome sequencing (WGS) was performed on the proband, followed by Sanger sequencing for co-segregation analysis with 22 family members. Multiple bioinformatics tools were used to assess evolutionary conservation, and AlphaFold3 modeling was employed to predict the potential impact on protein structure. Based on the genetic findings, prenatal diagnosis was subsequently offered to and performed for a female carrier in the family. Results A hemizygous ANOS1:c.1879T>C (p.Ser627Pro) variant was identified. Among the eight males with clinical features of KS in this family, five of whom underwent genetic testing, and all carried the variant. The variant fully co-segregated with KS among the genotyped individuals: all five tested males carried the variant (with their mothers confirmed as carriers), while five unaffected male relatives were wild-type. Bioinformatics analysis predicted that the variant site is evolutionarily conserved across species. AlphaFold3 modeling further suggested that the p. Ser627Pro substitution disrupts the original hydrogen bonding network, potentially leading to protein instability and function impairment. Based on these genetic findings, prenatal diagnosis was performed for a female carrier in the family, and the results showed that the fetus did not carry the variant. Conclusion Combining family co-segregation (PP1) and population frequency data (PM2), the ANOS1 c.1879T>C variant was classified as likely pathogenic, providing important information for genetic counseling. This study demonstrated that even in the absence of functional experiments, comprehensive family analysis can provide crucial clues for variant of uncertain significance (VUS) interpretation. This study also guided prenatal diagnosis, offering a referable strategy for the management of similar rare diseases.
Xiulan Hao, Yanchou Ye, Man Liu et al.· Frontiers in Genetics· 0 citations
ABSTRACT Background Hearing loss is one of the most common sensory disorders caused by genetic and environmental factors. Autosomal recessive non‐syndromic hearing loss (ARNSHL) is extremely heterogeneous, with over 100 genes known to be involved. Hearing loss can result from mutations in the LOXHD1 gene, which codes a highly conserved protein known as lipoxygenase and is located at 18q21.1. Despite the association between LOXHD1 mutations and ARNSHL, there are still few documented cases. Methods We examined a case of non‐syndromic hearing loss in an Iranian family with a history of consanguinity and several affected siblings. Next‐generation sequencing (NGS) was conducted on the proband to discover causal genetic alterations. Sanger sequencing was employed to confirm the identified variation. Results A novel likely pathogenic variant in the LOXHD1 gene, c.3713dupA (p.Asp1238Glufs*10), was identified. Sanger sequencing was used to confirm that the affected family members had this frameshift mutation. Conclusion Our findings broaden the mutational range of LOXHD1 linked to ARNSHL. This unique variant enhances the comprehension of the genetic underpinnings of hearing loss and may aid in molecular diagnostics and genetic counseling for impacted families.
Solmaz Hassani Fard Katiraei, Milad Gholami, Mohsen Soosanabadi et al.· Journal of clinical laborato...· 0 citations