title: 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.
authors: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
authors: Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology (KUST), Kohat, Khyber Pakhtunkhwa, Pakistan.
authors: Saadullah
authors: S
authors: Khan
authors: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
authors: Imran
authors: I
authors: Ullah
authors: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
authors: Abdul
authors: A
authors: Nasir
authors: Department of Radiology, MC Haaglanden, The Hague, The Netherlands.
authors: C Arnoud
authors: CA
authors: Meijer
authors: Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
authors: Marlies
authors: M
authors: Laurense-Bik
authors: Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
authors: Johan T
authors: JT
authors: den Dunnen
authors: Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
authors: Claudia A L
authors: CA
authors: Ruivenkamp
authors: Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
authors: Mariëtte J V
authors: MJ
authors: Hoffer
authors: Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
authors: Gijs W E
authors: GW
authors: Santen
authors: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
authors: Wasim
authors: W
authors: Ahmad
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis* / Q000235:genetics*; D000293:Adolescent; D002531:Cerebellum / Q000002:abnormalities*; D002648:Child; D000072661:Ciliopathies / Q000175:diagnosis* / Q000235:genetics*; D004252:DNA Mutational Analysis; D059472:Exome; D005124:Eye Abnormalities / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D009154:Mutation; D010154:Pakistan; D010375:Pedigree; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D040641:Quantitative Trait Loci; D011859:Radiography; D012160:Retina / Q000002:abnormalities*; D055815:Young Adult
chemical_list: C509165:MKS1 protein, human; D011506:Proteins
keywords: Joubert syndrome; MKS1 gene; exome sequencing; in-frame deletion; phenotypic variation; sanger sequencing