SETD5 heterozygous loss-of-function (LoF) variants and 3p25.3 deletions containing the SETD5 gene cause intellectual developmental disorder, autosomal dominant 23 (MRD23). We report five patients with an MRD23 phenotype caused by SETD5 missense variants. We studied patients with de novo SETD5 missense variants. A comprehensive literature search was conducted to reveal additional reports of SETD5 missense and LoF variants. Phenotypes and protein localization of missense variants were reviewed and compared to those reported for SETD5 LoF variants and 3p25.3 deletions. Computational analysis of the potential effect of SETD5 missense variants was performed. Six patients with de novo SETD5 missense variants were identified across five centers, gathered through the Deciphering Developmental Disorders (DDD) study database; four additional individuals with missense variants were reported in the DDD database. A comprehensive literature search revealed 12 unique individuals with missense variants, and 104 individuals with LoF variants or 3p25.3 deletions. One of the variants, p.Arg348Gln, recurred independently in three unrelated individuals. All patients with likely pathogenic missense variants shared dysmorphic features, GDD and autism, consistent with MRD23, but no major congenital anomalies, apart from hydrocephalus, which was a novel feature observed. Heart defects were reported only in the LoF group. Unlike LoF variants, which are scattered throughout the entire SETD5 coding region, pathogenic missense variants were confined to the protein's SET domain. We show that disease-causing missense variants in SETD5 cluster at the protein’s SET domain. This expands the mutation spectrum of the SETD5-related neurodevelopmental phenotype, providing a framework for improving both postnatal and prenatal genetic diagnostics.
While genetic heritability plays a major role in the development of cognitive impairment, most genetic risk factors are identified from studies of European populations. We conducted a genome-wide association study (GWAS) on cognitive impairment in the Chinese population by sequencing 1,040 matched case-control individuals from a longitudinal cohort of Zhejiang Province, China. We detected 19 SNPs clustered in 15 genomic loci reaching suggestive significance (P < 1 × 10− 5). Eleven of these genomic loci are newly associated with Alzheimer’s disease (AD) or cognitive impairment, among which five (GRP39, FAT1, EDIL3, ZNF596, and PDGFD) show nominal evidence of replication in both external GWAS of AD in East-Asian populations and summary statistics of AD in diverse populations. The detected loci are implicated in micronutrient homeostasis including zinc (GPR39), iron (STEAP1), potassium (KCNJ6), and vitamin K (VKORC1L1), cell connections (EVPLL) through cadherin regulations (PCDH18, FAT1), regulating amyloid-beta precursor protein (APP) (EDIL3), formation of amyloid-β (EDEM1) and neurofibrillary tangles (PDGFD, ZNF596), neuronal growth (NEGR1), and phosphatase regulations (SETBP1, TPTE). This study presents a robust GWAS for cognitive impairment in the Chinese population and highlights a promising set of therapeutic targets for neurodegenerative disorder.
Depression is one of the most common and disabling non-motor symptoms in Parkinson’s disease (PD), yet its genetic basis remains poorly understood. Here, we investigate the genetic contributions to depression in PD by estimating the burden from common as well as low-frequency single nucleotide polymorphisms (SNPs) within genes previously implicated in PD or depression risk among European ancestry PD patients from three population-based studies. Using gene-based association analyses (SKAT, Burden, and SKAT-O) in the PASIDA, PEG, and PPMI studies, we evaluated SNP sets in gene regions previously linked to PD or depression. Among PD-related genes, meta-analysis identified a significant association between KRTCAP2 and self-reported depression diagnosis in PD (SKAT-O p = 4.33 × 10⁻⁵), which remained significant after false discovery rate correction. A higher genetic burden in KRTCAP2 was associated with 20
Constitutional chromosomal heteromorphisms are common cytogenetic variants involving constitutive heterochromatin and acrocentric short-arm structures whose visual identification and classification remain challenging in routine cytogenetic practice. This study evaluated interobserver reliability in the visual classification of constitutional chromosomal heteromorphisms and characterized differences between homologous chromosomes using digital morphometry. A retrospective cross-sectional study included peripheral blood cytogenetic studies performed between 2021 and 2024. Sixty-six cases with previously reported heteromorphisms were included, yielding 73 heteromorphism observations. Four cytogeneticists, blinded to the original classification and clinical information, independently evaluated selected Q-banded metaphases using predefined visual criteria. Interobserver agreement was assessed using Krippendorff’s alpha and Gwet’s AC1. Digital morphometric analysis was performed in Fiji by measuring the chromosomal region associated with each heteromorphism, defined as the target region (TR), and calculating its absolute size and its ratio to total chromosome size (TR/T). Homologous chromosomes were compared using the Wilcoxon signed-rank test. Overall observed agreement was 70.1
Skeletal dysplasias are a diverse group of genetically inherited bone disorders which may manifest with or without short stature. Extreme short stature can also result from different growth hormone deficiencies. Our research aimed to identify the genetic causes of recessively inherited short stature, with or without skeletal abnormalities in Pakistani families. We recruited participants from thirty-eight pedigrees with a history of these disorders. Radiological examinations were performed for a few patients. Some samples were first screened for variants in GHRHR and RMRP by Sanger sequencing. Next, exome sequencing was carried out for selected patients from each family. Exome data were annotated and all were analyzed using Franklin software while some data were also analyzed using the 3billion automated system. Candidate variants were confirmed by segregation analyses in each family. We identified ten novel homozygous variants in AARS2, COL2A1, ERCC6, EVC2, GHR, IHH, MYH3, NPR2, OBSL1 and TG segregating with the phenotypes in ten different families. In-silico analyses predicted these variants to be deleterious to the genes or the encoded proteins. AARS2 variants have not been previously described to cause short stature. Members of the other twenty-five families had variants in nine different genes. A GHRHR founder mutation accounted for short stature without skeletal abnormalities in 12 families. In contrast, significant genetic heterogeneity was observed in the group of families with short stature accompanied by skeletal dysplasia. In conclusion, our study has broadened the genotypic and phenotypic spectrum of multiple genes and the associated diseases with short stature and skeletal dysplasia.
