Neurodevelopmental disorders (NDDs) are heterogeneous genetic conditions of the central nervous system (CNS). Primary phenotypes of NDDs include epilepsy, loss of developmental skills, abnormal movements, muscle weakness, ocular anomalies, hearing problems, and macro-or microcephaly. NDDs occur due to variants in genes encoding proteins involved in the structure and function of CNS, thus interrupting its normal physiological role. In the study presented here, four consanguineous families (A-D), with members showing neurodevelopmental symptoms, were recruited for clinical and genetic characterization of the phenotypes. Clinical examinations, including Seguin Form Board Test (SFBT), Vineland Social Maturity Scale (VSMS), brain Magnetic Resonance Imaging (MRI), Electroencephalogram (EEG), Electromyography (EMG), Nerve Conduction Velocity (NCV), and Magnetic Resonance Asmat Ullah and Abid Ali Shah contributed equally to the study.

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BackgroundProgressive spastic ataxia is a heterogeneous disorder characterized by cerebellar ataxia and limb spasticity associated with other severe neurological complications. Spastic ataxia is classified into pure and complex types, inherited in both an autosomal recessive and autosomal dominant manner. It is caused by pathogenic variants in at least eight different genes, including NKX6‐2 (MIM 607063) located on chromosome 10q26.3. The present study aimed to identify the genetic variant(s) underlying progressive spastic ataxia and to establish the genotype–phenotype correlation.MethodsWe collected a large consanguineous family having four affected individuals segregating progressive spastic ataxia in an autosomal recessive manner. To investigate the molecular cause of the disease, genomic DNA of three affected individuals underwent whole exome sequencing.ResultsAll of the affected individuals showed progressive clinical features such as spastic ataxia, lower limb weakness and other mild neurological abnormalities. Whole exome sequencing data were analyzed using different filters. Filtering of rare and shared homozygous variants revealed a novel homozygous missense variant (c.545C>T; p.Ala182Val) in a highly conserved homeobox domain of the NKX6‐2 protein.ConclusionsThe findings of the present study add a novel variant to the NKX6‐2 mutation spectrum and provide evidence that homozygous variants in the NKX6‐2 cause progressive spastic ataxia associated with other abnormalities.

Papillon-Lefèvre syndrome (PLS) is a rare genetic disorder of skin that runs in families in an autosomal recessive fashion. The typical disease symptoms include the thick