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.
Thi Bich Tuyen Ho, Alicia Coudert, Thi Thuy Hang Do et al.· Clinical Genetics· 0 citations
Multiple morphological abnormalities of the flagella (MMAF) is a severe form of male infertility characterized by immotile spermatozoa with absent, short, coiled, or irregular flagella. Despite advances in whole-exome sequencing, many cases remain genetically unexplained. Here, we identify a homozygous truncating variant in LRGUK (c.1063C>T; p.Arg355Ter) in an infertile man presenting with a typical MMAF phenotype. The variant, identified by whole-exome sequencing in a cohort of 168 MMAF patients and confirmed by Sanger sequencing, is predicted to result in loss of the C-terminal guanylate kinase-like domain. Immunofluorescence showed absence of LRGUK protein in patient spermatozoa, supporting a loss-of-function effect. Semen analysis revealed impaired motility and complete teratozoospermia. Morphological and ultrastructural analyzes demonstrated severe defects affecting both sperm head and flagellum, including disorganized axonemal architecture and central pair abnormalities. Nuclear analyzes showed increased nuclear size, defective chromatin compaction, and elevated DNA fragmentation. Immunostaining further indicated alterations of central apparatus-associated proteins, supporting a role for LRGUK in C1b projection organization. These findings identify LRGUK as a novel gene involved in male infertility, essential for spermatid morphogenesis and flagellum assembly.
Wiâme Mokkedem, Zeinab Wehbe, A. Barbotin et al.· Clinical Genetics· 0 citations
NFIC-related disorder represents a novel neurodevelopmental syndrome characterized by intellectual disability and macrocephaly, highlighting the importance of NFIC dosage supporting a mirror-syndrome model.
Nathalie Vanden Eynde, L. Hérissant, E. Landais et al.· Clinical Genetics· 0 citations