Two novel mutations in RNU4ATAC in two siblings with an atypical mild phenotype of microcephalic osteodysplastic primordial dwarfism type 1

Abstract

Taybi–Linder syndrome or microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1) (MIM # 210710) is a rare autosomal recessive developmental disorder, originally described in 1967 (Taybi and Linder, 1967). The patients present with severe intrauterine and postnatal growth retardation, microcephaly, facial dysmorphism, sparse thin hair and dry skin (Meinecke and Passarge, 1991). Radiological findings include dysplasia of the skeleton with cleft vertebral arches, horizontal acetabula and short and bowed long bones (Sigaudy et al., 1998). Neurological findings typically include profound developmental delay, blindness, hearing deficits, central nervous system malformations, early-onset epilepsy and neuroendocrine dysfunction (Pierce and Morse, 2012). MOPD1 has been shown to result from biallelic mutations in the RNU4ATAC gene encoding the small nuclear RNA (snRNA) U4atac, which is a component of the minor spliceosome. Although accounting for splicing of only about 800 introns, the minor spliceosome is involved in the correct splicing of many essential gene products. Thus, minor intron splicing has a critical role in human development (He et al., 2011). At present, only around 40 patients with MOPD1 and 10 different RNU4ATAC mutations have been reported according to the Human Gene Mutation Database. The condition is usually severe, and the patients do not generally live beyond the age of 3 years (Meinecke and Passarge, 1991). A few cases with a slightly milder phenotype have been reported (Abdel-Salam et al., 2012; Nagy et al., 2012), but no patients have yet been reported to survive into adulthood. We report on two adult siblings with MOPD1 presenting with an atypical mild phenotypic appearance compared with the previously reported cases.