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Hypomorphic MKS1 mutation in a Pakistani family with mild Joubert syndrome and atypical features: Expanding the phenotypic spectrum of MKS1-related ciliopathies.
. 2016 12; 170(12):3289-3293.

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+Show Affiliations

Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology (KUST), Kohat, Khyber Pakhtunkhwa, Pakistan.Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.Department of Radiology, MC Haaglanden, The Hague, The Netherlands.Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands.Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands.Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands.Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands.Department of Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands.Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.

Pub Type(s)

Case Reports
Journal Article

Language

eng

PubMed ID

27570071

Citation

Irfanullah, et al. "Hypomorphic MKS1 Mutation in a Pakistani Family With Mild Joubert Syndrome and Atypical Features: Expanding the Phenotypic Spectrum of MKS1-related Ciliopathies." American Journal of Medical Genetics. Part A, vol. 170, no. 12, 2016, pp. 3289-3293.
Irfanullah, Khan S, Ullah I, et al. Hypomorphic MKS1 mutation in a Pakistani family with mild Joubert syndrome and atypical features: Expanding the phenotypic spectrum of MKS1-related ciliopathies. Am J Med Genet A. 2016;170(12):3289-3293.
Khan, S., Ullah, I., Nasir, A., Meijer, C. A., Laurense-Bik, M., den Dunnen, J. T., Ruivenkamp, C. A., Hoffer, M. J., Santen, G. W., & Ahmad, W. (2016). Hypomorphic MKS1 mutation in a Pakistani family with mild Joubert syndrome and atypical features: Expanding the phenotypic spectrum of MKS1-related ciliopathies. American Journal of Medical Genetics. Part A, 170(12), 3289-3293. https://doi.org/10.1002/ajmg.a.37934
Irfanullah, et al. Hypomorphic MKS1 Mutation in a Pakistani Family With Mild Joubert Syndrome and Atypical Features: Expanding the Phenotypic Spectrum of MKS1-related Ciliopathies. Am J Med Genet A. 2016;170(12):3289-3293. PubMed PMID: 27570071.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hypomorphic MKS1 mutation in a Pakistani family with mild Joubert syndrome and atypical features: Expanding the phenotypic spectrum of MKS1-related ciliopathies. AU - ,, AU - Khan,Saadullah, AU - Ullah,Imran, AU - Nasir,Abdul, AU - Meijer,C Arnoud, AU - Laurense-Bik,Marlies, AU - den Dunnen,Johan T, AU - Ruivenkamp,Claudia A L, AU - Hoffer,Mariëtte J V, AU - Santen,Gijs W E, AU - Ahmad,Wasim, Y1 - 2016/08/29/ PY - 2016/03/01/received PY - 2016/08/05/accepted PY - 2016/8/30/pubmed PY - 2017/10/27/medline PY - 2016/8/30/entrez KW - Joubert syndrome KW - MKS1 gene KW - exome sequencing KW - in-frame deletion KW - phenotypic variation KW - sanger sequencing SP - 3289 EP - 3293 JF - American journal of medical genetics. Part A JO - Am. J. Med. Genet. A VL - 170 IS - 12 N2 - 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. SN - 1552-4833 UR - https://www.unboundmedicine.com/medline/citation/27570071/Hypomorphic_MKS1_mutation_in_a_Pakistani_family_with_mild_Joubert_syndrome_and_atypical_features:_Expanding_the_phenotypic_spectrum_of_MKS1_related_ciliopathies_ L2 - https://doi.org/10.1002/ajmg.a.37934 DB - PRIME DP - Unbound Medicine ER -