RTTN Mutations Cause Primary Microcephaly and Primordial Dwarfism in Humans

Abstract

Primary microcephaly is a developmental brain anomaly that results from defective proliferation of neuroprogenitors in the germinal periventricular zone. More than a dozen genes are known to be mutated in autosomal-recessive primary microcephaly in isolation or in association with a more generalized growth deficiency (microcephalic primordial dwarfism), but the genetic heterogeneity is probably more extensive. In a research protocol involving autozygome mapping and exome sequencing, we recruited a multiplex consanguineous family who is affected by severe microcephalic primordial dwarfism and tested negative on clinical exome sequencing. Two candidate autozygous intervals were identified, and the second round of exome sequencing revealed a single intronic variant therein (c.2885+8A>G [p.Ser963(∗)] in RTTN exon 23). RT-PCR confirmed that this change creates a cryptic splice donor and thus causes retention of the intervening 7 bp of the intron and leads to premature truncation. On the basis of this finding, we reanalyzed the exome file of a second consanguineous family affected by a similar phenotype and identified another homozygous change in RTTN as the likely causal mutation. Combined linkage analysis of the two families confirmed that RTTN maps to the only significant linkage peak. Finally, through international collaboration, a Canadian multiplex family affected by microcephalic primordial dwarfism and biallelic mutation of RTTN was identified. Our results expand the phenotype of RTTN-related disorders, hitherto limited to polymicrogyria, to include microcephalic primordial dwarfism with a complex brain phenotype involving simplified gyration.

Ethical and counseling challenges in prenatal exome sequencing

“…Exome sequencing revealed two missense variants (compound heterozygous) of uncertain significance in the RTTN gene. Pathogenic variants in the RTTN gene have been reported in children with microcephaly, brain abnormalities, and primordial dwarfism, a phenotype that overlapped with ultrasound findings in our case …”

Genetics and mechanisms leading to human cortical malformations

“…The most severe outcomes of PMG occur in children with severe microcephaly (-3 SD or smaller). Patients with severe congenital microcephaly and PMG have for example, shown mutations in WDR62 (WD repeat-containing protein 62), NDE1, RTNN and RAB3GAP1/2 and RAB18 [240][241][242]. PMG with microcephaly or normal brain size, corpus callosum dysgenesis and cerebellar hypoplasia may also be related to tubulin and MT-motor gene mutations such as KIF1B binding protein, TUBA1A, TUBB, TUBB2B, TUBB3, and DYNC1H1 (see Tables 1 and 2) [156,199,237].…”

GOLGA2, encoding a master regulator of golgi apparatus, is mutated in a patient with a neuromuscular disorder

“…We have previously shown that research-grade whole exome sequencing can uncover causal mutations that are missed by clinical exome sequencing (Ben-Omran et al 2015; Shaheen et al 2015; Shamseldin et al 2015). Therefore, we enrolled this patient in a research protocol that entails combined autozygome/exome analysis.…”