Biallelic truncating DNAH14 variant in siblings with neurodevelopmental disorder and predominant ataxia: clinical report and literature review

Abstract

Neurodevelopmental disorders (NDDs) with ataxia are genetically heterogeneous and remain a diagnostic challenge. Recent advances in genomic technologies have facilitated the identification of rare, potentially causative variants in genes not traditionally associated with classic NDD phenotypes. The DNAH14 gene, encoding a dynein axonemal heavy chain involved in ciliary motility, has recently emerged as a novel candidate in neurological syndromes. Here, we report two Turkish siblings presenting with late-onset balance disorder, progressive ataxia, and cognitive impairment. Initial genetic analysis revealed that both siblings also harbor FXN GAA repeat expansions consistent with pathogenic Friedreich's ataxia (FRDA). To elucidate the molecular basis of the patients' cognitive impairment, whole-exome sequencing was performed. This analysis identified a novel homozygous frameshift variant in the DNAH14 gene, located within the conserved linker domain upstream of the motor core, which is critical for ATP hydrolysis and microtubule interactions. The variant is absent from population databases, predicted to be deleterious by multiple in silico algorithms, and segregates in the family in a manner consistent with autosomal recessive inheritance. The coexistence of FRDA expansions and a truncating DNAH14 variant suggests a potential dual genetic contribution to the observed phenotype, in which FRDA-associated pathology likely underlies the ataxia, while DNAH14 disruption may contribute to additional neurodevelopmental features. This is the first report describing the co-occurrence of FRDA and a homozygous truncating DNAH14 variant in the same individuals, broadening our understanding of overlapping neurogenetic mechanisms. Our findings expand the phenotypic spectrum of DNAH14-related disorders and highlight the importance of considering multilocus pathogenic variants in patients with complex or atypical ataxia presentations.