Hypomorphic MKS1 mutation in a Pakistani family with mild Joubert syndrome and atypical features: Expanding the phenotypic spectrum of MKS1‐related ciliopathies

Abstract

Postaxial polydactyly (PAP) is one of the most common congenital malformations observed in the general population. However, it can also occur as part of a syndrome. Unbiased genetic screening techniques such as exome sequencing are highly appropriate methods to provide a molecular diagnosis in patients with polydactyly due to the large number of mutated genes associated with it. The present study describes a consanguineous family of Pakistani origin with PAP, speech impairment, hearing impairment of variable degree, and proportionate short stature with no prominent intellectual disability or ophthalmological abnormalities. One affected individual of the family was subjected to exome sequencing which resulted in the identification of four homozygous variants including an in-frame deletion (c.1115_1117delCCT; p.(Ser372del) in MKS1, which was later shown to be the only variant segregating with the phenotype. In silico predictions supported the potential pathogenicity of the identified mutation. Additional clinical tests and MRI features of a patient in the family showed a molar tooth sign, which is a hallmark of Joubert syndrome. In conclusion, we have described a pathogenic variant in the MKS1 resulting in a mild Joubert syndrome phenotype, which broadens the spectrum of mutations in the MKS1. © 2016 Wiley Periodicals, Inc.

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 ].…”

“…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 ].…”

Meckel–Gruber Syndrome: An Update on Diagnosis, Clinical Management, and Research Advances

“…More generally, MKS1 mutations are associated with higher rates of polydactyly and occipital encephalocele, bone dysplasia, cleft palate, and situs defects ( 52 ). All MKS1 mutations reported in MKS patients are null mutations, but a hypomorphic mutation has been reported in an individual with BBS ( 48 ), and recently in individuals with JBTS ( 53 , 54 ).…”

Atypical, milder presentation in a child with CC2D2A and KIDINS220 variants

“…This may be partly due to the fact that initial studies focused on severe developmental delay phenotypes but with wider access to next-generation sequencing, patients with non-distinctive, milder phenotypes are having more advanced genetic testing. Joubert syndrome and its associated genes are no exception (Irfanullah et al, 2016;Méjécase et al, 2019).…”