KIF1A novel frameshift variant p.(Ser887Profs*64) exhibits clinical heterogeneity in a Pakistani family with hereditary sensory and autonomic neuropathy type IIC.
| Autor: | Ghafoor S; Translational Genomics Laboratory, COMSATS University Islamabad, Pakistan., Rafiq MA; Translational Genomics Laboratory, COMSATS University Islamabad, Pakistan.; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada., Abbas Shah ST; Translational Genomics Laboratory, COMSATS University Islamabad, Pakistan., Ansar M; Institute of Molecular and Clinical Ophthalmology, Basel, Switzerland., Paton T; Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.; The Centre for Applied Genomics (TCAG), The Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, Toronto, Ontario, Canada., Ajmal M; Translational Genomics Laboratory, COMSATS University Islamabad, Pakistan., Agha Z; Translational Genomics Laboratory, COMSATS University Islamabad, Pakistan., Qamar R; Pakistan Academy of Sciences, Islamabad, Pakistan.; Science and Technology Sector, ICESCO, Rabat, Morocco., Azam M; Translational Genomics Laboratory, COMSATS University Islamabad, Pakistan. |
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| Jazyk: | angličtina |
| Zdroj: | The International journal of neuroscience [Int J Neurosci] 2024 Jun; Vol. 134 (6), pp. 665-675. Date of Electronic Publication: 2022 Nov 08. |
| DOI: | 10.1080/00207454.2022.2140428 |
| Abstrakt: | Background: Hereditary sensory and autonomic neuropathies (HSANs) are rare heterogeneous group of neurological disorders caused by peripheral nerve deterioration. The HSANs sub-clinical classes have clinical and genetic overlap which often lead to misdiagnosis. In the present study a Pakistani family with five affected members suffering from severe neuropathy were genetically analyzed to identify the disease causative element in the family. Methods: Genome wide high-density single nucleotide polymorphism (SNP) microarray analysis was carried out followed by whole exome sequencing of the affected proband and another affected sibling. Shared homozygous regions in all severely affected members were identified through homozygosity mapping approach. Results: The largest homozygous region of 14.1 Mb shared by the five severely affected members of the family was identified on chromosome 2. Subsequent exome sequencing identified a novel single nucleotide deletion c.2658del; p.(Ser887Profs*64) in KIF1A . Segregation analysis revealed that this mutation was homozygous in all five affected individuals of the family with severe clinical manifestation, while members of the family that were heterozygous carriers shared abnormal skin features (scaly skin) only with the homozygous affected members. Conclusions: A novel frameshift mutation p.(Ser887Profs*64) in KIF1A is the potential cause of severe HSANIIC in a Pakistani family along with incomplete penetrance in mutation carriers. We demonstrate that using a combination of different techniques not only strengthens the gene finding approach but also helps in proper sub-clinical characterization along with identification of mutated alleles exhibiting incomplete penetrance leading to intrafamilial clinical variability in HSAN group of inherited diseases. |
| Databáze: | MEDLINE |
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