Whole-exome sequencing identifies homozygous mutation in TTI2 in a child with primary microcephaly: a case report

Abstract

Background: Primary microcephaly is defined as reduced occipital-frontal circumference noticeable before 36 weeks of gestation. Large amount of insults might lead to microcephaly including infections, hypoxia and genetic mutations. More than 16 genes are described in autosomal recessive primary microcephaly. However, the cause of microcephaly remains unclear in many cases after extensive investigations and genetic screening. Case presentation: Here, we described the case of a boy with primary microcephaly who presented to a neurology clinic with short stature, global development delay, dyskinetic movement, strabismus and dysmorphic features. We performed microcephaly investigations and genetic panels. Then, we performed whole-exome sequencing to identify any genetic cause. Microcephaly investigations and genetic panels were negative, but we found a new D317V homozygous mutation in TELOE-2 interacting protein 2 (TTI2) gene by whole-exome sequencing. TTI2 is implicated in DNA damage response and mutation in that gene was previously described in mental retardation, autosomal recessive 39. Conclusions: We described the first French Canadian case with primary microcephaly and global developmental delay secondary to a new D317V homozygous mutation in TTI2 gene. Our report also highlights the importance of TTI2 protein in brain development.

System genetics in the rat HXB/BXH family identifies Tti2 as a pleiotropic quantitative trait gene for adult hippocampal neurogenesis and serum glucose

“…dysmorphic facial features, short stature, speech and movement disorders, and skeletal deformations[72,[84][85][86]. Similar abnormalities were observed in children carrying TELO2 mutations[87,88].…”

Functional analysis of a novel de novo variant in PPP5C associated with microcephaly, seizures, and developmental delay

“…Compound heterozygous variants in TELO2 (the human homolog of yeast Tel2) have been identified in six probands, including three siblings and three unrelated individuals, with You-Hoover-Fong syndrome, which is characterized by microcephaly, movement disorder, and severe delayed development (You et al 2016). Recently, a proband with microcephaly was identified to have a homozygous missense variant in TTI2 , further implicating ATR, HSP90 and TTT complex in microcephaly (Picher-Martel et al 2020). Given that PPP5C is highly expressed in the mammalian brain, and overexpression and knockdown studies showed hyper- and hypo-cellular proliferation, respectively, it is tempting to hypothesize that a reduction of PPP5C function as seen with the variant Ala47Thr could lead to microcephaly and other neurodevelopmental abnormalities observed in the proband (Zuo et al 1998; Lv et al 2018).…”

Updates on Clinical and Genetic Heterogeneity of ASPM in 12 Autosomal Recessive Primary Microcephaly Families in Pakistani Population

“…The parents and some of the siblings of the homozygous patients are heterozygous carriers for these ASPM variants, whereas other siblings are homozygous for the wild-type allele, which corresponds to the recessive inheritance pattern of MCPH in these families. ASPM mutations result in abnormal spindle-like microcephaly-associated protein, which is responsible for 40 to 68% of MCPH incidence ( 17 , 18 ).…”