Aug 2026· Clinical Genetics· 0 citations· 31 references
Medicine
TL;DR
This work collected cases of HTX investigated by trio-based whole-exome (WES) and whole-genome sequencing (WGS) and performed detailed clinical and molecular characterization in seven children and fetuses from France and Vietnam and revealed significant phenotypic heterogeneity while highlighting strong genotype-phenotype correlations.
Abstract
Heterotaxy (HTX) is a rare condition characterized by complex congenital heart defects and a wide spectrum of extracardiac abnormalities that significantly impact survival. While molecular diagnosis is essential for clinical management, next-generation sequencing (NGS) currently identifies disease-causing variants in only 20%-30% of HTX cases. To address this diagnostic gap, we collected cases of HTX investigated by trio-based whole-exome (WES) and whole-genome sequencing (WGS) and performed detailed clinical and molecular characterization in seven children and fetuses from France and Vietnam. In parallel, we conducted a systematic review of 108 published cases to refine genotype-phenotype correlations. We identified seven variants in four key genes: DNAH9, PKD1L1, MMP21, and GDF1. The findings revealed significant phenotypic heterogeneity while highlighting strong genotype-phenotype correlations, such as the association of MMP21 and GDF1 variants with severe conotruncal malformations. Two unreported variants were identified, further expanding the mutational spectrum of laterality defects. By integrating fetopathological data with advanced genomic analyses, we further delineate the phenotypic spectrum of these conditions. Ultimately, this work underscores the high diagnostic value of NGS in prenatal and neonatal cardiology, enabling earlier diagnosis and more personalized clinical management.
BACKGROUND
Whole exome sequencing (WES) has improved diagnostic rates for neurodevelopmental disorders (NDDs) while introducing challenges in novel variant interpretation. DHX30-related NDD (DHX30-NDD) is a recently described condition with an evolving phenotypic spectrum.
OBJECTIVES
To expand the understanding of the DHX30-NDD genotype-phenotype spectrum by integrating a case-based WES interpretation with a scoping review.
METHODS
We performed comprehensive genetic analysis (karyotyping, microarray, WES) on a proband with global developmental delay (GDD). A systematic literature search of PubMed/MEDLINE, Scopus and Google Scholar from database inception to April 2026 identified 10 publications including 51 individuals with DHX30-NDD. Clinical and genetic data were extracted to characterize the genotype-phenotype spectrum.
RESULTS
The proband presented with GDD and right microtia, harbouring a de novo heterozygous pathogenic DHX30 missense variant (c.1478G > A; p.Arg493His), confirming DHX30-NDD. To our knowledge, this is the first reported individual with DHX30-NDD and microtia. The scoping review confirmed DHX30 variants are formed predominantly de novo and affected both sexes (22 males; 29 females). Hallmark manifestations were motor delay (50/51; 98.0%), GDD/ID (48/49; 98.0%), hypotonia (48/51; 94.1%), feeding difficulties (38/51; 74.5%), ataxia (17/23; 73.9%), abnormal brain imaging (36/49; 73.5%) and absent expressive language (35/48; 72.9%). Digital anomalies (31/51; 60.8%), eye anomalies (28/51; 54.9%), autistic behaviours (24/44; 54.5%), sleep disturbances (26/51; 51.0%), joint hypermobility (25/51; 49.0%), microcephaly (23/51; 45.1%) and ear anomalies (22/51; 43.1%) were also frequent.
CONCLUSIONS
This study potentially expands the phenotypic spectrum of DHX30-NDD, highlights the clinical utility of WES for diagnosing GDD and underscores the importance of ongoing WES reanalysis for evolving variant interpretation.
Nattaporn Tassanakijpanich, Areerat Hnoonual, Oradawan Plong-On et al.· Journal of Intellectual Disa...· 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
16p11.2 microduplication syndrome (OMIM #614671) is a pathogenic recurrent copy-number gain at the 16p11.2 locus and is associated with variable expressivity across neurodevelopmental, growth, and medical phenotypes. Gastrointestinal symptoms have been reported in carrier cohorts, but detailed documentation of gastrointestinal motility and neuromuscular findings remains limited. We performed clinical and genetic analyses in a multigenerational family in which the proband (III1) presented with limb muscle pain, exercise intolerance, and chronic gastrointestinal symptoms. Next-generation sequencing (NGS), low-pass whole-genome sequencing (lpWGS)-based CNV analysis, Sanger sequencing, and qPCR validation identified a 0.8 Mb microduplication at 16p11.2 (BP4-BP5), involving 44 genes including TBX6, inherited from the mother (II2). The proband's clinical manifestations included developmental delay, pointed chin, low body mass index, gastrointestinal dysfunction (chronic abdominal pain, diarrhea, esophageal motility disorder, and rectal prolapse), forward-leaning gait, mild scoliosis, and limb muscle atrophy with inflammatory muscle involvement. Four family members (II2, III1, III2, and III4) carried the microduplication, but their available clinical features varied in severity and system involvement. The proband's twin brother (III2) had left ear deafness and epilepsy, individual II2 had blindness from cone-rod dystrophy, and III4 showed more pronounced scoliosis. This family provides a detailed clinical and genetic description of 16p11.2 microduplication carriers with prominent gastrointestinal motility and neuromuscular manifestations, thereby enriching the clinical characterization of this recurrent CNV and supporting substantial intrafamilial phenotypic heterogeneity.
OBJECTIVE
This study was undertaken to characterize the clinical and genetic spectrum of RHOBTB2-related disorders (RHOBTB2-RDs) in a Chinese population, explore genotype-phenotype correlations, and develop a refined clinical framework to improve diagnosis and management.
METHODS
We conducted a comprehensive analysis by integrating data from 12 Chinese patients (five retrospective, seven from literature) with 79 international cases from published studies. Genetic analysis focused on variant classification and hotspot identification. Standardized phenotypic data extraction was performed, followed by systematic classification and correlation analyses.
RESULTS
In the Chinese cohort, all variants were de novo missense mutations, with 75% in the Broad-complex, Tramtrack, and Bric-à-brac (BTB) domain and conserved hotspots (e.g., p.Arg483His). Across the combined cohort (N = 91), RHOBTB2-RDs presented a broad phenotypic spectrum. As an exploratory proposal, we introduce paroxysmal encephalopathy with weakness (PEW) as a potential novel clinical phenotypic cluster, strongly associated with BTB domain variants. A practical subtyping framework was proposed: the BTB subtype (severe developmental and epileptic encephalopathy [DEE] with prominent paroxysmal features, often necessitating aggressive seizure management), the truncating/splicing subtype (primarily intellectual disability/developmental delay and movement disorders with epilepsy, requiring focused neurodevelopmental support), the guanosine triphosphatase subtype (a mixed phenotype with a generally more favorable neurodevelopmental course), and the interdomain subtype (frequently associated with PEW alongside DEE or paroxysmal movement disorders).
SIGNIFICANCE
This study systematically characterizes RHOBTB2-RDs in Chinese patients, confirming conserved pathogenic hotspots across ethnicities and identifying population-specific features. The proposed clinical subtyping framework and PEW diagnostic criteria provide valuable tools for improving diagnostic accuracy and guiding personalized management of RHOBTB2-RDs.
Ming Liu, Xiao-Juan Tian, Yu-Pin Ma et al.· Epilepsia· 0 citations
Background and Objectives: Male factors account for approximately 30–50% of subfertile couples. Teratozoospermia is one of the major causes of male infertility; however, the genetic factors underlying many cases remain incompletely understood. This study aimed to identify potential genetic variants associated with teratozoospermia and to investigate the possible involvement of Caudal-Type Homeobox 4 (CDX4) in sperm morphogenesis. Materials and Methods: Whole-exome sequencing was performed in 44 individuals with teratozoospermia. A rare CDX4 variant (NM_005193.2, c.103G>T; NP_005184.1, Gly35Cys) was identified and confirmed by Sanger sequencing. Because CDX4 is located on the X chromosome, this variant was interpreted as hemizygous in the male patient. Sperm morphology, CDX4 localization, public GEO transcriptomic data (GSE6969), and CDX4 expression during murine spermiogenesis were analyzed. Results: The CDX4 p.Gly35Cys variant is located within the Caudal-like transactivation domain, a conserved region involved in transcriptional regulation. Spermatozoa from the patient carrying this variant exhibited severe morphological abnormalities, predominantly involving sperm-head defects, together with aberrant CDX4 localization along the midpiece and tail, in contrast to the neck- and annulus-enriched distribution observed in control spermatozoa. Reanalysis of the GEO dataset showed increased CDX4 transcript levels in teratozoospermic samples compared with normozoospermic controls. During murine spermiogenesis, CDX4 was detected in the nuclei of spermatogonia and spermatocytes and subsequently localized to the sperm head and neck/tail regions during sperm morphogenesis. Conclusions: CDX4 c.103G>T (p.Gly35Cys) is a rare hemizygous X-linked candidate variant associated with severe teratozoospermia in a single patient. Further cohort-based, segregation, and functional studies are required to clarify its role in sperm morphogenesis.
C. Au, Ya-Yun Wang, T. Lai et al.· Medicina· 0 citations
Hypospadias is one of the most common birth defects in China and a key feature of differences in sex development (DSD), yet its genetic etiology remains largely unresolved. Current diagnostic approaches using DSD-targeted gene panels have a low rate of definitive diagnoses (5.5%), highlighting the need for more comprehensive genetic investigation. In this study, we performed next-generation sequencing (NGS) on the largest trio-based cohort of hypospadias to date, comprising 106 pediatric cases and their parents (92 trios). We achieved a definitive genetic diagnosis in 6.6% of patients, identifying pathogenic variants in canonical DSD genes such as AR, NR5A1 and WT1. By incorporating a broader spectrum of potentially clinically significant variants, we increased the overall genetic identification rate to 33.0% (35/106). Strikingly, trio analysis uncovered a significant burden of de novo loss-of-function (LoF) variants (2.2-fold enrichment, P=0.001), primarily driven by variants in genes associated with ciliopathies (10.35-fold, P=0.016), a previously underappreciated gene class in hypospadias. Furthermore, we identified and functionally validated two high-confidence risk genes, PRKCZ and HRNR, based on recurrent de novo variants. Functional assays confirmed that these variants disrupt key biological mechanisms, including cell proliferation, migration, and androgen signaling. Our large-scale trio approach substantially expands the genetic landscape of hypospadias, demonstrates the critical value of trio-based sequencing for improving diagnostic yield, and decisively implicates ciliary genes in its pathogenesis.
Yan-Qin You, Yingliu Luo, Hong-Hui Zhou et al.· Science China Life Sciences· 0 citations
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