Four novel compound heterozygous mutations in C5orf42 gene in patients with pure and mild Joubert syndrome

Abstract

Joubert syndrome (JS) is a rare neurodevelopmental disorder. It is mainly characterized by developmental delay, hypotonia/ ataxia and a specific cerebral magnetic resonance imaging (MRI) finding called "molar tooth sign" (MTS) (Romani, Micalizzi, & Valente, 2013). MTS is a distinctive cerebellar and brainstem defect in axial plane of cranial MRI comprising thickened, elongated and straight superior cerebellar peduncles (SCP), deepened interpeduncular fossa (IF), and accompanied by cerebellar vermis hypoplasia (CVH). JS patients present with varying degree of cognitive impairment, abnormal breathing patterns or oculomotor apraxia, and variable abnormalities in other systems. It can be manifested as purely neurological phenotype or be accompanied by extra-neurological symptoms including encephalocele, polydactyly, orofacial defects, retinal dystrophy and colobomas, cystic kidney disease, and liver fibrosis (Bachmann-Gagescu et al., 2015; Valente, Dallapiccola, & Bertini, 2013). JS is a genetically heterogeneous ciliopathy caused by aberrant

Clinical heterogeneity and intrafamilial variability of Joubert syndrome in two siblings with CPLANE1 variants

“…Since 2012, multiple variants of CPLANE1 have been identified in JBTS families by using WES (Alazami et al, 2012; Asadollahi et al, 2018; Kroes et al, 2016; Liu et al, 2020; Ohba et al, 2013; Srour et al, 2012). Meanwhile, several novel variants of CPLANE1 have been reported to be responsible for the OFD VI and milder type of JBTS phenotypes (Bayram et al, 2015; Bonnard et al, 2018; Lopez et al, 2014; Romani et al, 2015; Wentzensen et al, 2015).…”

Novel compound heterozygous CPLANE1 variants identified in a Chinese family with Joubert syndrome

“…In a more recent study, Liu et al. (2020) identified four novel compound heterozygous mutations in CPLANE1 in four Chinese families with JS, exhibiting pure JS clinical manifestations and mild neuroradiological features. Their findings indicate that CPLANE1 mutations generally result in a purely neurological JS phenotype and mild brain defects, rather than OFD VI.…”

“…Due to the limitations of epidemiological surveys in China, more family studies have been conducted in European countries. A total of 207 cases with JS have been reported in China, including pathogenic variants of CPLANE1, TMEM67, MKS1, CC2D2A, AHI1, ARMC9, CEP290, NPHP1, ARL13B, B9D2, CSPP1, INPP5E, PIBF1, RPGRIPIL, and TCTN1( Liu et al., 2020; Xiang et al., 2018 ) . Eight JS cases caused by CPLANE1 mutations have been identified, covering more than 10 mutation sites (Table 1) (Liu et al., 2020; Xiang et al., 2018).…”

“…A total of 207 cases with JS have been reported in China, including pathogenic variants of CPLANE1, TMEM67, MKS1, CC2D2A, AHI1, ARMC9, CEP290, NPHP1, ARL13B, B9D2, CSPP1, INPP5E, PIBF1, RPGRIPIL, and TCTN1( Liu et al., 2020; Xiang et al., 2018 ) . Eight JS cases caused by CPLANE1 mutations have been identified, covering more than 10 mutation sites (Table 1) (Liu et al., 2020; Xiang et al., 2018). Most of the pathogenic sites are located within the coding region, but there are no concentrated mutation hotspots.…”

Exome sequencing and RNA analysis identify two novel CPLANE1 variants causing Joubert syndrome

“…According to our research, the novel c.7534-14G > A variant is classified as likely pathogenic (PS3 + PM2_Supporting+PM3 + PP3). Since 2012, more and more variants of CPLANE1 have been identified in JS families (Liu et al, 2020;Zhu et al, 2021). WES has proved to be a powerful tool for the identification of novel variants in JS (Koyama et al, 2017).…”