Sateesh Maddirevula

Samra, Sharma, et al. identify biallelic loss-of-function variants in OSMR as the cause of a new human primary atopic disorder characterized by severe early-onset eczema, eosinophilia, and elevated IgE. Loss of OSMRβ surface expression abolishes OSM-dependent STAT signaling, revealing a key role for OSM-OSMR signaling in maintaining cutaneous immune homeostasis.

Pediatric dilated cardiomyopathy (DCM) carries high morbidity and mortality, with up to half of cases genetically unexplained. The mTORC1 nutrient sensing pathway is a critical regulator of cardiomyocyte homeostasis, yet no Mendelian DCM genes have been linked to its upstream regulator, GATOR2. WDR59 encodes a core WD‐repeat subunit of GATOR2, but its cardiac role is unknown. We recruited six affected individuals from four unrelated families presenting with early‐onset, severe autosomal recessive syndromic DCM. Affected children developed left ventricular dilation, variably accompanied by cataracts, dysmorphic facial features, and growth and developmental delay. Saudi patients mapped to a single locus and shared therein a homozygous founder WDR59 variant: c.2887G>A (p.Gly963Arg). The French patient was compound heterozygous for two variants (NM_030581.4:c.966+3A>G and NM_030581.4:c.886+1219T>G) and their deleterious splicing effect was confirmed by RNA‐seq. We propose WDR59 as a novel autosomal recessive DCM gene and implicate dysregulated GATOR2–mTORC1 signaling as the underlying mechanism. Future validation is needed to confirm this link and investigate whether restoring mTORC1–autophagy balance can ameliorate WDR59 ‐related cardiac dysfunction.

STEAP3 (Six‐transmembrane epithelial antigen of the prostate 3), a metalloreductase, plays a key role in various cell processes, including iron homeostasis, inflammation, and cancer promotion. Over a decade ago, researchers reported a single, heterozygous nonsense variant in STEAP3 linked to transfusion‐dependent severe hypochromic anemia. However, a later large population study on STEAP3 found no phenotypic red cell changes in heterozygous individuals. While the genotype and phenotype of STEAP3 are tentatively established for hypochromic microcytic anemia with autosomal dominant inheritance (MIM: 615234), we describe an autosomal recessive form of STEAP3 ‐related neonatal familial hemophagocytic lymphohistiocytosis (HLH). We expanded the phenotype to include cytopenia and neonatal HLH. Our report on two affected male siblings highlights the expanded phenotype, clarifies the phenotypic spectrum of STEAP3 , and broadens its genetic inheritance, ultimately providing a clinical and molecular workup for neonatal patients with unexplained HLH.

Cerebral palsy (CP) is a neurodevelopmental disorder of motor function, with genetic etiologies, particularly de novo variants, identified in approximately one-third of cases. The contribution of consanguinity – long-recognized as a CP risk factor – has remained undefined. Here, we report findings from 188 primarily consanguineous Middle Eastern families with CP and identified putative causative genes in nearly three-quarters. The majority demonstrated recessive inheritance, although multi-level consanguinity and multilocus pathogenic variants complicated Mendelian assortment analyses. We identified 110 known CP-associated genes – five with phenotypic expansions and three others exhibiting new recessive inheritance patterns – and 24 novel candidates. We characterized ten candidates as high-confidence based on independent replication and protein modeling. We experimentally validated a role for SUCO variants in CP and newly identified a role for mid-gestational migrating excitatory neurons in the disorder. These findings highlight new genes, pathways, and phenotypes that reveal striking genomic diversity in CP.

Background: Chromosomal aneuploidy, characterized by an abnormal number of chromosomes, represents a significant cause of genetic disorders. While karyotyping and chromosomal microarray analysis (CMA) are established diagnostic approaches, they are limited by cost and extended turnaround times. Advances in exome sequencing (ES) bioinformatics enable detection of chromosomal aneuploidy alongside single-nucleotide variant analysis. This study explores the utility of clinical ES for the detection of aneuploidies. Method: We analyzed exome sequencing data (2023–2024) from samples positive for Trisomy 21 (n = 27), Trisomy 18 (n = 4), Turner syndrome (n = 3), and Klinefelter syndrome (n = 2) from our clinical ES cohort (n = 10,000). Results: The results obtained were concordant with copy number variants (CNVs) identified by clinical testing. Conclusion: In conclusion, our findings suggest that exome sequencing offers a rapid and viable approach for the detection of chromosomal aneuploidy, potentially reducing turnaround time and associated costs.

Brain development requires the coordinated growth of structures and cues that are essential for forming neural circuits and cognitive functions. The corpus callosum, the largest interhemispheric connection, is formed by the axons of callosal projection neurons through a series of tightly regulated cellular events, including neuronal specification, migration, axon extension and branching. Defects in any of those steps can lead to a range of disorders known as syndromic corpus callosum dysgenesis (CCD). We report five unrelated families carrying bi-allelic variants in WDR47 presenting with CCD together with other neuroanatomical phenotypes such as microcephaly and enlarged ventricles. Using in vitro and in vivo mouse models and complementation assays, we show that WDR47 is required for survival of callosal neurons by contributing to the maintenance of mitochondrial and microtubule homeostasis. We further propose that severity of the CCD phenotype is determined by the degree of the loss of function caused by the human variants. Taken together, we identify WDR47 as a causative gene of a new neurodevelopmental syndrome characterized by corpus callosum abnormalities and other neuroanatomical malformations.