Aug 2026· Biomolecules· Vol 16· 0 citations· 56 references
Medicine
TL;DR
The results further demonstrate the genetic heterogeneity of MAC, while supporting the involvement of complex inheritance and/or environmental factors in many of the cases.
Abstract
Microphthalmia, anophthalmia and ocular coloboma (MAC) are rare developmental eye disorders. Although over 100 causative genes have been identified, the molecular spectrum and genotype–phenotype correlations remain incompletely understood, particularly in genetically diverse populations. We set out to molecularly characterize MAC in the Israeli population. Forty-seven MAC-affected individuals from 43 unrelated families were enrolled. DNA of all probands was subjected to whole exome sequencing. The most common phenotype was microphthalmia (64% of patients). Definite or possible molecular diagnoses were achieved in 13/43 probands (30%) and involved 10 different genes (MFRP, SMO, GJA8, SOX2, RARB, TSPAN12, SHH, PTPN11, BEST1, and TP63). An in vitro splicing assay was used to explore the pathogenicity of a variant in the SMO gene. Following stringent filtering of exome data, 226 rare possibly pathogenic variants were identified in 218 genes not previously associated with MAC. The rate of molecular diagnosis achieved in this Israeli MAC cohort is similar to the reported range in other studies. The results further demonstrate the genetic heterogeneity of MAC, while supporting the involvement of complex inheritance and/or environmental factors in many of the cases. Further studies are required to reveal these underlying etiological factors, and to support the novel genotype–phenotype associations suggested here.
It is demonstrated that early-onset MORC2-associated disorders segregate into two principal neurological phenotypes: a predominantly neuromuscular form and a central nervous system-predominant form.
A. Murtazina, Eugenii Tatarsky, I. Viakhireva et al.· Journal of Medical Genetics· 0 citations
The discovery of variants in PTEN, SRCAP, PQBP1, and NOG identifies novel candidate genes and uncovers potential disease mechanisms in craniosynostosis.
Yu-Feng Huang, Lingyue Huang, Li-Lin Hu et al.· Frontiers in Genetics· 0 citations
This study expands the mutational landscape of JS in the Iranian population and underscores the utility of WES as a first-tier diagnostic tool for JS and related ciliopathies.
Sheyda Khalilian, Mohadeseh Fathi, Zahra Farbood et al.· Molecular Genetics and Metab...· 0 citations
BACKGROUND
Non-syndromic hereditary hypotrichosis (NSHH) is a genetically heterogeneous disorder characterized by sparse or absent hair growth. Comprehensive genotype-phenotype correlation analyses remain limited, particularly in the Chinese population.
OBJECTIVES
To define the genetic and phenotypic spectrum of NSHH in a Chinese cohort and to explore genotype-phenotype correlations with potential clinical utility.
METHODS
This observational multicenter study included 47 unrelated families (107 affected individuals) with clinically and genetically confirmed NSHH. Genetic analysis was performed using next-generation sequencing with Sanger validation. Clinical features, including age at onset, severity, hair shaft morphology, and extracranial hair involvement, were systematically analysed and correlated with causative genes.
RESULTS
Eleven causative genes were identified in 47 unrelated families, with LIPH (n=18, 38.3%), LSS (n=10, 21.27%), and HRURF (n=7, 14.89%) being the most prevalent. NSHH showed marked phenotypic heterogeneity with genotype-dependent patterns in age at onset, severity, and hair shaft morphology. Congenital onset was common in LIPH, LSS, and HRURF, whereas postnatal onset was observed in APCDD1, KRT86, and HR. Preliminary genotype-phenotype analysis of LIPH demonstrated allele-specific effects, with c.736T>A associated variants linked to more severe hypotrichosis compared with c.742C>A. In HRURF, two recurrently affected regions were observed, involving the start codon and the region encoding amino acids 23-28. Based on these findings, a preliminary phenotype-driven candidate-gene prioritisation framework was proposed. Exploratory analysis of topical minoxidil showed variable treatment responses.
CONCLUSIONS
This study defines the genetic architecture and genotype-phenotype correlations of NSHH in the Chinese population and provides a preliminary phenotype-driven framework that may assist clinical evaluation and candidate-gene prioritisation.
An-Qi Zhao, Qiao-Yu Cao, Han Chen et al.· British Journal of Dermatolo...· 0 citations
ABSTRACT Background Anophthalmia/microphthalmia (A/M) is a severe congenital ocular malformation characterized by the complete absence or small size of the eye bulb. Interpreting copy number variations (CNVs) in A/M is challenged by variable genotype–phenotype correlations and reduced penetrance. This study investigated the genetic etiology of A/M‐associated CNVs. Methods Genomic profiling was performed on four unrelated families presenting with ocular anomalies or harboring A/M‐susceptible CNVs. Variants were evaluated by integrating American College of Medical Genetics and Genomics (ACMG) guidelines with clinical phenotypes and familial segregation. Results An inherited 8.13 Mb deletion (8p23.3p23.1) in Patient 1 was excluded due to genotype–phenotype mismatch. Patients 2 and 3 harbored de novo pathogenic deletions involving OTX2 (14q22.3) and SOX2 (3q26.33), causing typical A/M. Case 4 revealed a 14q22.2q23.1 deletion encompassing OTX2 in a fetus and mother without ocular anomalies, consistent with the incomplete penetrance of OTX2‐related microphthalmia. Thus, CNV‐induced haploinsufficiency causes A/M with high phenotypic variability. Conclusion Accurate CNV interpretation requires robust genotype–phenotype correlation and careful assessment of incomplete penetrance to prevent diagnostic pitfalls and improve genetic counseling.
Sotos syndrome is an overgrowth disorder caused by heterozygous NSD1 variants, partial-gene deletions, or 5q35 microdeletions. Malan syndrome, a phenotypically overlapping condition, results from haploinsufficiency of the NFIX gene due to either heterozygous chromosomal microdeletions involving the 19p13.2 region or heterozygous loss-of-function variants. This multicenter study aimed to characterize the clinical and molecular features of individuals with Sotos and Malan syndromes in Türkiye. We retrospectively analyzed clinical and molecular data from 48 individuals with genetically confirmed Sotos or Malan syndrome across 14 centers. Molecular analyses included whole-exome sequencing, clinical exome sequencing, targeted gene panels, multiplex ligation-dependent probe amplification, and chromosomal microarray analysis. Forty-two individuals were diagnosed with Sotos syndrome and six with Malan syndrome. All exhibited characteristic facial features, and 97.9% had developmental delay or intellectual disability. We identified a total of 38 NSD1 variants, of which 35 were classified as pathogenic or likely pathogenic and three as variants of uncertain significance; notably, 23 of these variants were novel. Three patients carried 5q35 microdeletions, and one had an intragenic deletion involving exons 10-11. Four distinct NFIX variants (two novel) were detected in five patients, and one carried a 19p13.13 deletion encompassing the entire gene. This nationwide study expands the genotype-phenotype spectrum of Sotos and Malan syndromes in Türkiye and supports improved diagnostic and clinical management strategies.
Ceren Yılmaz Uzman, Semra Gürsoy, F. Hazan et al.· Clinical Genetics· 0 citations
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