A Common Ancestral Asn242Ser Mutation in <b><i>TMEM67</i></b> Identified in Multiple Iranian Families with Joubert Syndrome

Abstract

Background: Joubert syndrome (JS) is a clinically and genetically heterogeneous group of rare neurodevelopmental disorder characterised by peculiar midbrain-hindbrain malformation, known as the “molar tooth” sign. JS can manifest a broad range of signs and symptoms. The most common features of JS are hypotonia, ataxia, developmental delay/intellectual disability, abnormal eye movements, and neonatal breathing abnormalities. To date, 29 genes have been shown to cause JS. Methods: We employed whole-genome single nucleotide polymorphism genotyping in a group of Iranian families with JS and Sanger sequencing of a known mutation associated with JS located in a single homozygous regions shared by affected members of the families. Results: Homozygosity mapping uncovered a shared ∼2.2-Mb run of homozygosity on chromosome 8q21.3-q22.1 encompassing the known JS-causing TMEM67 gene. Sanger sequencing of a known mutation (NM_153704.5: c.725A>G; p.Asn242Ser) in TMEM67 identified from studying another Iranian family using whole-exome sequencing confirmed the presence of the homozygous mutation in 22 affected members of 12 nuclear families. “Molar tooth” sign of brain magnetic resonance imaging, moderate-to-severe neurodevelopmental delay, and abnormal eye movements were the most common features of affected individuals. In addition, liver disease, seizure, behavioural abnormalities, failure to thrive, and kidney disease were observed variably in some of the patients. Conclusion: We propose that Asn242Ser is a founder mutation in the Iranian population, which might explain a significant proportion of JS cases from eastern Iran. Therefore, screening for this variant should be considered for genetic testing in Iranian patients with JS. In addition, this finding is important for developing population-specific genetic testing in Iran.

Novel compound heterozygous TMEM67 variants in a Vietnamese family with Joubert syndrome: a case report

“…Whole exome sequencing identified compound heterozygous TMEM67 variants in the proband (II:1). The variant c.725A > G p.Asn242Ser was previously documented in patients with JS and predicted to be pathogenic by SIFT, Polyphen-2 and Mutation Taster [21]. This variant was considered as founder mutation in Eastern Iranian population.…”

Genotype–phenotype correlates in Joubert syndrome: A review

“…Conversely, biallelic variants in CC2D2A seem to be more commonly associated with seizures (Bachmann‐Gagescu et al, 2012). Several additional genes have been occasionally found mutated in JS patients with epilepsy, including the commonly mutated AHI1, KIAA0586, MKS1 , and TMEM67 , as well as many other rarely mutated genes (Bachmann‐Gagescu, Dempsey, et al, 2015; Bader et al, 2016; Dehghani et al, 2017; Inskeep et al, 2022; Kroes et al, 2016; Rafiullah et al, 2017; Sivathanu et al, 2020; Sumathipala et al, 2020; Van De Weghe et al, 2017; Wentzensen et al, 2016).…”

Anomalies of Midbrain/Hindbrain Development and Related Disabilities: Pontocerebellar Hypoplasia, Congenital Disorders of Glycosylation, and Cerebellar Hemisphere Hypoplasia

“…Therefore, screening for this variant should be considered for genetic testing in Iranian patients with JS. 108 The overall evidence provides support for the important role of cerebellar structures by themselves in shaping emotional, cognitive, and linguistic development when vermian lesions are associated with cerebellar hemispheric lesions. 109 In contrast, lesions of the cerebellar worm and brain stem appear to have a major impact on motor skills, including oromotor skills and verbal working memory.…”