Due to the emerging links between tRNA modification and neurodevelopmental processes, we next investigated whether DALRD3 is associated with any neurological disorders of unknown genetic etiology. We identified a consanguineous family with two sibling patients exhibiting profound global developmental delay and persistent early infantile epilepsy who tested negative for known disease mutations by routine karyotype, chromosomal microarray, and an epilepsy gene panel (Fig. 6a). The family was identified by applying a “genomics first” approach to uncharacterized patients with neurodevelopmental disorders50. Parents are healthy first cousins and they have one healthy child in addition to the two affected children and one spontaneous miscarriage (Fig. 6b). Subsequent exome sequencing guided by autozygome analysis51 revealed a single homozygous nucleotide substitution resulting in a C to A transversion in exon 9 of the DALRD3 gene in a shared region of autozygosity between the two affected siblings on chromosome 3 (Fig. 6c). Confirmatory Sanger sequencing validated the full segregation of this variant with the disease in the family in a fully penetrant autosomal-recessive model, being homozygous in both patients and heterozygous in the parents and
