Recurrent RTTN mutation leading to severe microcephaly, polymicrogyria and growth restriction

Heterogeneous clinical phenotypes and cerebral malformations reflected by rotatin cellular dynamics

“…In Family H, a homozygous variant c.[2953A>G] was found by whole exome sequencing, affecting the penultimate nucleotide in exon 23 of RTTN , identical to that reported in Families C and D (Grandone et al , 2016; Cavallin et al , 2018). Aberrant splicing was reported in Families C and D and verified in this study.…”

“…Following our report in 2012 of RTTN mutations in individuals with intellectual disability and cerebral polymicrogyria, additional subjects have been described with a different clinical presentation, including other brain malformations (primary microcephaly), growth defects and congenital anomalies (Kheradmand Kia et al , 2012; Shamseldin et al , 2015; Grandone et al , 2016; Rump et al , 2016; Vora et al , 2017; Cavallin et al , 2018; Chartier et al , 2018; Stouffs et al , 2018; Wambach et al , 2018). The phenotypic spectrum that emerges after reviewing all clinical reports with bi-allelic RTTN variants has been summarized in Table 1 and shows that the most common, although not obligate, features are severe intellectual disability, lack of speech and primary microcephaly.…”

“…Germline variants in RTTN have been reported in 13 families, with a total of 23 affected individuals (Kheradmand Kia et al , 2012; Shamseldin et al , 2015; Grandone et al , 2016; Rump et al , 2016; Vora et al , 2017; Cavallin et al , 2018; Chartier et al , 2018; Stouffs et al , 2018; Wambach et al , 2018). Here we report three additional families, including five affected individuals, and two novel recessive alterations in RTTN.…”

“…The cortical malformation is often predominant in frontal regions, suggesting elective underdevelopment of frontal lobes (Fig. 1) (Cavallin et al , 2018). Normal pressure hydrocephalus, prominent in Rttn −/− knockout mice, is also present in several individuals (Shamseldin et al , 2015) (Family I, Supplementary Table 2).…”

“…Genetic alterations in rotatin, encoded by the RTTN (OMIM #610436) gene, were originally linked to autosomal recessive polymicrogyria in two families, but were later also associated with primary microcephaly and primordial dwarfism in additional families (Kheradmand Kia et al , 2012; Shamseldin et al , 2015; Grandone et al , 2016; Rump et al , 2016; Vora et al , 2017; Cavallin et al , 2018; Chartier et al , 2018; Stouffs et al , 2018; Wambach et al , 2018). Studies in human fibroblasts allocated rotatin to the basal body of the primary cilium, suggesting involvement of the protein in primary ciliogenesis and sonic hedgehog (SHH) signalling (Kheradmand Kia et al , 2012; Wambach et al , 2018).…”