Notable Genomics Research

(Human Genetics and Genomics Advances 6, 100479; October 9, 2025)

Obesity and obesity-related traits have a major impact on global health. While a myriad of genes and variants have been associated with these traits, substantial functional work still needs to be performed to understand the underlying molecular mechanisms. In this issue, Baya et al. identify genes associated with obesity and fat distribution using exome sequencing from the UK Biobank and test their function in a human adipocyte cell line. Using rare variant gene burden tests, the authors find 69 genes associated with traits, including body mass index (BMI), waist-to-hip ratio adjusted for BMI, and body fat percentage.

Using genetic data from >1,200 South Africans, we examine admixture patterns from Cape Town to the historic colonial frontier’s northern edge, finding male-biased European ancestry and female-biased Khoe-San ancestry. While admixture among all sources has likely been continuous around Cape Town, we find varying patterns further from the colonial center.

RNA sequencing in rare disease is conventionally used to resolve the effect of a variant on a single gene. Here, we apply a transcriptome-wide approach to detect disorders of the minor spliceosome. Thus, examining transcriptome-wide signatures can increase diagnostic yield, provide variant-to-function interpretation of spliceopathies, and uncover additional gene-disease associations.

This genome-wide study reveals novel and shared genetic factors underlying four major eye diseases and their comorbidities. Integrating Mendelian randomization and functional analyses, this study uncovers a causal role for depression in cataract development, offering insights into systemic influences on ocular health and potential precision medicine targets.

Allele-specific RNA interference silences the mutant PACS1 transcript causing Schuurs-Hoeijmakers syndrome, a rare neurodevelopmental disorder. RNA sequencing of cells from affected individuals revealed extracellular matrix defects corrected by siRNA treatment, providing a promising therapeutic approach for this dominant inherited disease with no current treatment.

Bi-allelic INTU gene variants disrupt ciliogenesis and cilia signaling, leading to a pleiotropic syndrome characterized by craniofacial anomalies, cardiac defects, and developmental delays. Functional studies support a causal role, reinforcing the link between INTU dysfunction and human ciliopathies, and improving clinical interpretation of INTU-related genetic findings.

The Karnataka Genome Project has facilitated chromosome-level assembly of an individual using blood samples from Karnataka, India, challenging genome assemblies from non-primary cell lines. The four other reference genomes reported here representing east, west, north, and south elevates South Asia to a level playing field in advancing genomic research.

Mutations in seven aminoacyl-tRNA synthetase cause dominant neurological disease with varying severity. To date, a unifying mechanism has not been identified for these related phenotypes. This study demonstrates that dominant NARS1 variants have dominant-negative (DN) properties. Furthermore, the study provides evidence that variable DN effects explain the observed clinical heterogeneity.

The HBOP VCEP developed PALB2-specific ACMG/AMP variant interpretation guidelines by tailoring, limiting, or removing existing codes. Testing on 39 pilot variants improved concordance with ClinVar and reclassified several variants of uncertain significance. These conservative, evidence-based specifications will support harmonized, accurate PALB2 variant classification in the public domain.

RetiGene is an expert-curated atlas of genes involved in inherited retinal diseases, integrating variant data and gene expression. This open-access, continually updated resource aims to support variant interpretation, gene panel design, and future therapeutic research.

Tomar et al. study N-glycan branching in the intestine during Crohn disease. A common variant in the manganese transporter, ZIP8 causes manganese insufficiency and increases Crohn disease risk. Glycosyltransferases require manganese. N-Glycosylation can be augmented with oral N-acetylglucosamine with improved gut homeostasis, avoiding risks posed by direct manganese supplementation.

SOD1 variants cause the motor neuron disease amyotrophic lateral sclerosis. Axakova et al. functionally assay ∼86% of all possible SOD1 missense variants, producing a variant-effect map resource that quantitatively correlates with human phenotypes, yields insights into sequence-structure-function relationships, and provides evidence for interpreting clinical variants.

(The American Journal of Human Genetics 111, 1383–1404; July 11, 2024)

Mosaic loss of the Y chromosome (mLOY) is the most common somatic mutation in men. Its frequency increases with age, and it is associated with various diseases. Here, we present MosCoverY, a method that allows the identification and quantification of mLOY from exome and whole-genome sequencing data.