Identification of a Novel Splice-Site variant in TACR3 (c.888 + 1G > A) Associated with Asthenozoospermia and Hypogonadotropic Hypogonadism in an Iranian Family.
A previously unreported splice-site mutation in TACR3 that likely causes familial infertility by disrupting the neurokinin B/NK3R signaling pathway is identified and extended the mutational landscape of TACR3 and highlight its essential contribution to male reproductive endocrinology.
Intellectual disability (ID) affects approximately 1-3% of the global population, with a higher prevalence reported in consanguineous populations due to autosomal recessive variants. The
C22orf31
gene is one of the important candidate genes that is expressed in the brain and is associated with global developmental delays and ID. We aimed to identify the genetic basis of ID, seizure, and microcephaly in a Saudi consanguineous family. Whole exome sequencing was performed on the affected individual from a consanguineous Saudi family, followed by Sanger validation and bioinformatics prediction. Our results showed a novel homozygous 5-base pair (bp) deletion NM_015370.1 (c.433-1_436delGAGTA; p.Ser145Lysfs*9) in the
C22orf31
gene. The gene is important and the identified mutation in the
C22orf31
gene may disrupt the canonical splice acceptor site and cause a frameshift, leading to a premature termination codon (PTC) that is predicted to trigger nonsense-mediated decay and complete protein loss. The patient manifested developmental delays and seizures along with microcephaly. In conclusion, we report a novel 5-bp deletion in the
C22orf31
gene in a Saudi patient. Functional studies and identification of additional families are needed to confirm the role of
C22orf31
in disease pathogenesis. This novel finding expands the mutational and clinical spectrum of
C22orf31
mutation-related neurodevelopmental disorders in Saudi Arabia.
Md. Safayet Hossain, O. Muthaffar, Angham Abdulrehman Abdulakreem et al.· Journal of Disability Resear...· 0 citations
Rare candidate variants in SSX1, CPNE1, and SPTBN5 that may potentially be associated with the molecular basis of oligoasthenoteratozoospermia are identified and support the application of WGS in unresolved male infertility.
Sara Sadeghzadeh, A. Malcher, Razieh Ebrahimi Askari et al.· Journal of Applied Genetics· 0 citations
Background/aim Cryptorchidism is the most common congenital anomaly of the male genitourinary system, characterized by a multifactorial etiology. The disheveled-associated activator of morphogenesis 2 (DAAM2) gene regulates androgen receptor (AR)-dependent transcription; its variants are associated with partial androgen insensitivity. Since the inguinoscrotal phase of testicular descent is androgen-dependent, we hypothesized that DAAM2 variants contribute to cryptorchidism susceptibility. This pilot study, designed to generate hypotheses rather than to establish association, investigated the frequency of two functionally characterized DAAM2 variants, p.(Asp165Glu) and p.(Asn614ThrfsTer2), in pediatric cryptorchidism. Materials and methods This prospective case-control study included 40 male pediatric cryptorchidism patients and 39 age- and sex-matched healthy male controls. Genomic DNA was extracted from peripheral blood. The p.(Asp165Glu) variant was genotyped by TaqMan allelic discrimination and p.(Asn614ThrfsTer2) by ARMS-PCR with melting curve analysis. Genotype distributions were compared using linear-by-linear association testing with exact p-values, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by binary logistic regression. Results Heterozygous p.N614Tfs*2 carriage was more frequent in cryptorchidism patients (12.5%, n = 5) than in controls (2.6%, n = 1), with an unadjusted OR of 5.43 (95% CI: 0.6048.78, p = 0.131). Heterozygous p.D165E frequency was similar in both groups (7.5% vs. 7.7%; OR: 1.03, 95% CI: 0.19–5.45, p = 0.974), whereas homozygous p.D165E was identified exclusively in 2 of 40 cryptorchidism patients (5.0%) and in none of the controls, resulting in complete separation in the regression model. Conclusion Although statistical significance could not be reached due to the limited size of the study group, the observed fivefold increase in heterozygosity of p.(Asn614ThrfsTer2) and the presence of homozygosity of p.(Asp165Glu) in cryptorchidism cases contribute to the literature. These data suggest that DAAM2 variants may play a potential role in the etiology of cryptorchidism.
Onur Yalçın, Çağrı Doğan· Turkish Journal of Medical S...· 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
BACKGROUND
Classical Ehlers-Danlos syndrome (cEDS), caused by pathogenic variants in COL5A2, is characterized by skin hyperextensibility, joint hypermobility and atrophic scarring. This study aimed to identify and validate the pathogenicity of an unreported COL5A2 intronic variant in a Chinese family with cEDS.
METHODS
Trio-based whole exome sequencing (Trio-WES) was performed to screen for pathogenic variants, and the candidate variant was confirmed by Sanger sequencing. Minigene assays were then conducted to evaluate the functional consequences of key variants.
RESULTS
A de novo COL5A2 (NM_000393.3) c.2499 + 4_2499 + 5insTAA variant was identified. Minigene assays demonstrated that this variant induced exon 37 skipping, resulting in an in-frame deletion. Based on ACMG guidelines, the variant was classified as pathogenic and considered the likely underlying etiology of cEDS in this family.
CONCLUSION
These findings expand the variant spectrum of COL5A2, improving molecular diagnosis of cEDS.
Familial hypercholesterolemia (FH) is an autosomal codominant disorder characterized by impaired clearance of low-density lipoproteins from the bloodstream, markedly elevated plasma total cholesterol and low density lipoprotein cholesterol levels, and early onset of atherosclerosis and cardiovascular disease. FH is one of the most common monogenic disorders in humans. The majority of FH cases are caused by pathogenic variants in three genes:
LDLR
(OMIM: 143890),
APOB
(OMIM: 107730), and
PCSK9
(OMIM: 607786). More than 80 % of FH cases are associated with mutations in the
LDLR
gene, located on chromosome 19. In 25–75 % of patients with a clinical FH phenotype, no pathogenic variant is identified in these genes. Whole-exome sequencing and targeted gene panel sequencing of the
LDLR
,
APOB
,
PCSK9
, and
LDLRAP1
genes were performed in patients with an FH phenotype, followed by confirmation of the identified variants by Sanger sequencing. Three unrelated probands were found to carry intronic
LDLR
variants for which functional evidence was previously unavailable. The aim of this study was to functionally assess
in vitro
the effects of three intronic
LDLR
variants (NM_000527.5: c.940+3_940+6del, c.941-3C>G, and c.2389+5G>A) on pre-mRNA splicing using a minigene assay. Minigene constructs encompassing target exons with flanking intronic sequences were generated and transfected into the HEK293 and HeLa cell lines. The deleterious effect of all three variants on pre-mRNA splicing was confirmed. The fournucleotide deletion c.940+3_940+6del resulted in two aberrant transcripts: inclusion of six nucleotides from intron 6 and complete retention of the minigene intronic sequence. The c.941-3C>G variant caused loss of the canonical acceptor splice site and activation of a cryptic site, with inclusion of intronic nucleotides from intron 6. The c.2389+5G>A variant resulted in exon 16 skipping. Functional
in vitro
analysis is a key tool for the molecular verification of intronic variants of uncertain clinical significance and, in conjunction with clinical data, supports the establishment of a definitive molecular diagnosis.
V. Danilchenko, D. Ivanoshchuk, O. Timoshchenko et al.· Vavilov Journal of Genetics...· 0 citations
