Expanding the phenotype of RTTN variations: a new family with primary microcephaly, severe growth failure, brain malformations and dermatitis

Abstract

Primary autosomal recessive microcephaly (MCPH) is a developmental disorder characterized by prenatal onset of abnormal brain growth. MCPH occurs both alone and as part of a broad range of neurodevelopmental syndromes with or without cortical malformations and growth retardation. Here we report a consanguineous Moroccan family with two siblings affected by severe primary microcephaly, failure to thrive, congenital dermatitis and severe developmental delay. Brain magnetic resonance imaging showed lissencephaly of frontal lobes and periventricular heterotopia of the gray matter. We performed both Comparative Genomic Hybridization array and whole exome sequencing (WES) analyses of the kindred. No quantitative defects were detected. However, WES identified a new homozygous missense variation in the penultimate nucleotide of exon 23 of RTTN gene (c.2953A>G;pArg985Gly). cDNA sequencing revealed two abnormal spliced products, one lacking only exon 23 and the other lacking exons 22 and 23 (out-of-frame). RTTN is a protein involved in cilia structure and function. Homozygous mutations in RTTN gene have been described in bilateral diffuse isolated polymicrogyria and, more recently, in microcephalic primordial dwarfism (PD). We found a novel homozygous mutation in RTTN associated with microcephalic PD as well as complex brain malformations and congenital dermatitis, thus expanding the phenotypic spectrum of both RTTN-associated diseases and ciliary dysfunction.

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 …”

“…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. 11,12 We believed that disclosure of the phenotype-proband overlap was in the best interests of the parents and potentially relevant to future reproductive decisions. The results were reported to the family with highly tailored counseling to explain the uncertainty of the results.…”

A neuropathological study of novel RTTN gene mutations causing a familial microcephaly with simplified gyral pattern

“…Patients presented with severe intellectual disability, microcephaly with various brain malformations, growth retardation and a broad spectrum of malformations of other organs. This microcephalic phenotype was confirmed in two other families (Grandone et al, 2016;Rump et al, 2015). The present case is clearly related to this microcephalic phenotype.…”

“…RTTN gene mutations (OMIM 614833) have been reported in patients with polymicrogyria associated with seizures (PMGWS) (Kheradmand Kia et al, ). More recently RTTN gene mutations have been reported in cases associating primary microcephaly with primordial dwarfism associated with malformations of the brain and other organs (Grandone et al, ; Rump et al, ; Shamseldin et al, ). Here, we report on the identification of two novel RTTN gene mutations in a family where recurrent microcephaly was associated with simplified gyral pattern and moderate growth retardation.…”

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].…”