Novel Compound Heterozygous Variants in MKS1 Leading to Joubert Syndrome

Abstract

Joubert syndrome (JBTS) and Meckel-Gruber syndrome (MKS) are rare recessive disorders caused by defects of cilia, and they share overlapping clinical features and allelic loci. Mutations of MKS1 contribute approximately 7% to all MKS cases and are found in some JBTS patients. Here, we describe a JBTS patient with two novel mutations of MKS1. Whole exome sequencing (WES) revealed c.191-1G > A and c.1058delG compound heterozygous variants. The patient presented with typical cerebellar vermis hypoplasia, hypotonia, and developmental delay, but without other renal/hepatic involvement or polydactyly. Functional studies showed that the c.1058delG mutation disrupts the B9 domain of MKS1, attenuates the interactions with B9D2, and impairs its ciliary localization at the transition zone (TZ), indicating that the B9 domain of MKS1 is essential for the integrity of the B9 protein complex and localization of MKS1 at the TZ. This work expands the mutation spectrum of MKS1 and elucidates the clinical heterogeneity of MKS1-related ciliopathies.

Case Report: Preimplantation Genetic Testing for Meckel Syndrome Induced by Novel Compound Heterozygous Mutations of MKS1

“…The MKS1 -related genotype–phenotype correlation was proposed as follows: two null alleles of MKS1 result in MKS; one null allele and one non-truncating allele that leaves the B9-C2 domain intact result in JBTS; two non-truncating alleles result in Bardet–Biedl syndrome (BBS, MIM 615990) ( Bader et al, 2016 ; Luo et al, 2020 ). Previous studies have identified the compound heterozygous mutations of MKS1 (p.R158* and p.E471Lfs*92), which disrupted the intracellular localization of MKS1 and induced defects in cilium length and the number of patient fibroblasts ( Slaats et al, 2016 ).…”

Mild Clinical Presentation of Joubert Syndrome in a Male Adult Carrying Biallelic MKS1 Truncating Variants

“…Biallelic MKS1 pathogenic variants have been described in few JBTS patients who usually harbor at least one non-truncating variant [ 5 , 12 , 13 , 14 , 16 , 17 ]. In contrast, biallelic truncating variants in MKS1 are associated with more severe ciliopathies, such as MKS [ 8 , 25 ].…”

“…In contrast, biallelic truncating variants in MKS1 are associated with more severe ciliopathies, such as MKS [ 8 , 25 ]. To date, only two reports described biallelic MKS1 truncating variants in individuals presenting a JBTS neurological phenotype with the distinctive ‘molar tooth sign’, hypotonia, developmental delay, intellectual disability, and dysmorphisms [ 16 , 17 ]. One of these patients (homozygous for the c.1461-2A>G splice-site variant, predicted in silico to introduce a PTC) had retinal dystrophy [ 17 ].…”

“…One of these patients (homozygous for the c.1461-2A>G splice-site variant, predicted in silico to introduce a PTC) had retinal dystrophy [ 17 ]. In the other index case, who was compound heterozygous for a frameshift (c.1058delG) and a splice-site mutation (c.191-1G>A), ophthalmological assessment was not performed [ 16 ]. Compared to these two cases, the patient herein described is significantly milder because of the lack of severe neurological manifestations, despite the presence of the pathognomonic ‘molar tooth sign’.…”

“…Although a clear genotype-phenotype correlation has not yet been established, loss-of-function MKS1 variants have been found to be responsible for approximately 7–13% of MKS cases [ 8 , 9 ], whereas hypomorphic MKS1 variants have been associated with milder clinical presentations, such as BBS [ 10 ] and JBTS [ 11 , 12 , 13 , 14 , 15 ]. As an exception to this correlation, biallelic truncating MKS1 variants have been detected in two JBTS individuals [ 16 , 17 ]. We report a further milder phenotype in an individual with adult-onset Retinitis Pigmentosa (RP) who was found to harbor biallelic nonsense variants in the MKS1 gene.…”