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BBS5 and INPP5E mutations associated with ciliopathy disorders in families from Pakistan

BBS5 and INPP5E mutations associated with ciliopathy disorders in families from Pakistan
BBS5 and INPP5E mutations associated with ciliopathy disorders in families from Pakistan
Ciliopathies are a clinically and genetically heterogeneous group of disorders often exhibiting phenotypic overlap and caused by abnormalities in the structure or function of cellular cilia. As such, a precise molecular diagnosis is important for guiding clinical management and genetic counseling. In the present study, two Pakistani families comprising individuals with overlapping clinical features suggestive of a ciliopathy syndrome, including intellectual disability, obesity, congenital retinal dystrophy, and hypogonadism (in males), were investigated clinically and genetically. Whole-exome sequencing identified the likely causes of disease as a novel homozygous frameshift mutation (NM_152384.2: c.196delA; p.(Arg66Glufs*12); family 1) in BBS5, and a nonsense mutation (NM_019892.5:c.1879C>T; p.Gln627*; family 2) in INPP5E, previously reported in an extended Pakistani family with MORM syndrome. Our findings expand the molecular spectrum associated with BBS5 mutations in Pakistan and provide further supportive evidence that the INPP5E mutation is a common cause of ciliopathy in Northern Pakistan, likely representing a regional founder mutation. This study also highlights the value of genomic studies in Pakistan for families affected by rare heterogeneous developmental disorders and where clinical phenotyping may be limited by geographical and financial constraints. The identification of the spectrum and frequency of disease-causing variants within this setting enables the development of population-specific genetic testing strategies targeting variants common to the local population and improving health care outcomes.
0003-4800
Khan, Shazia
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Lin, Siying
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Harlalka, Gaurav V.
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Ullah, Asmat
d0cf6d10-c417-44ad-a306-282fa6b81425
Shah, Khadim
fc9b9c6e-b4e1-4ccd-8e2f-47137c0215eb
Khalid, Sumbul
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Mehmood, Sarmad
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Hassan, Muhammad Jawad
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Ahmad, Raja Wasim
347d92aa-40d9-4c90-a9e0-7a721779cd68
Self, James
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Crosby, Andrew H.
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Baple, Emma L.
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Gul, Asma
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Khan, Shazia
ed88bc44-1ee7-4b57-8bcb-f8a52562fdf5
Lin, Siying
1bf515d9-21d4-4be5-bce8-f7a719143032
Harlalka, Gaurav V.
1417f12a-ae2a-40ff-9a26-bf37e7dd9578
Ullah, Asmat
d0cf6d10-c417-44ad-a306-282fa6b81425
Shah, Khadim
fc9b9c6e-b4e1-4ccd-8e2f-47137c0215eb
Khalid, Sumbul
27a59d0a-1ef3-4134-8043-9353730d129a
Mehmood, Sarmad
9b252623-07fa-419e-8019-7d70d58715df
Hassan, Muhammad Jawad
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Ahmad, Raja Wasim
347d92aa-40d9-4c90-a9e0-7a721779cd68
Self, James
0f6efc58-ae24-4667-b8d6-6fafa849e389
Crosby, Andrew H.
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Baple, Emma L.
3069a362-2742-42a5-a7a7-e92a9af6fa88
Gul, Asma
9aa14f1b-5258-4ef1-a6e2-9026a833f67d

Khan, Shazia, Lin, Siying, Harlalka, Gaurav V., Ullah, Asmat, Shah, Khadim, Khalid, Sumbul, Mehmood, Sarmad, Hassan, Muhammad Jawad, Ahmad, Raja Wasim, Self, James, Crosby, Andrew H., Baple, Emma L. and Gul, Asma (2019) BBS5 and INPP5E mutations associated with ciliopathy disorders in families from Pakistan. Annals of Human Genetics, [12336]. (doi:10.1111/ahg.12336).

Record type: Article

Abstract

Ciliopathies are a clinically and genetically heterogeneous group of disorders often exhibiting phenotypic overlap and caused by abnormalities in the structure or function of cellular cilia. As such, a precise molecular diagnosis is important for guiding clinical management and genetic counseling. In the present study, two Pakistani families comprising individuals with overlapping clinical features suggestive of a ciliopathy syndrome, including intellectual disability, obesity, congenital retinal dystrophy, and hypogonadism (in males), were investigated clinically and genetically. Whole-exome sequencing identified the likely causes of disease as a novel homozygous frameshift mutation (NM_152384.2: c.196delA; p.(Arg66Glufs*12); family 1) in BBS5, and a nonsense mutation (NM_019892.5:c.1879C>T; p.Gln627*; family 2) in INPP5E, previously reported in an extended Pakistani family with MORM syndrome. Our findings expand the molecular spectrum associated with BBS5 mutations in Pakistan and provide further supportive evidence that the INPP5E mutation is a common cause of ciliopathy in Northern Pakistan, likely representing a regional founder mutation. This study also highlights the value of genomic studies in Pakistan for families affected by rare heterogeneous developmental disorders and where clinical phenotyping may be limited by geographical and financial constraints. The identification of the spectrum and frequency of disease-causing variants within this setting enables the development of population-specific genetic testing strategies targeting variants common to the local population and improving health care outcomes.

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More information

Accepted/In Press date: 18 May 2019
e-pub ahead of print date: 7 June 2019

Identifiers

Local EPrints ID: 434111
URI: http://eprints.soton.ac.uk/id/eprint/434111
ISSN: 0003-4800
PURE UUID: 6f94a9db-a624-451b-9d61-16cf8d19f9c7
ORCID for James Self: ORCID iD orcid.org/0000-0002-1030-9963

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Date deposited: 12 Sep 2019 16:30
Last modified: 16 Mar 2024 03:47

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Contributors

Author: Shazia Khan
Author: Siying Lin
Author: Gaurav V. Harlalka
Author: Asmat Ullah
Author: Khadim Shah
Author: Sumbul Khalid
Author: Sarmad Mehmood
Author: Muhammad Jawad Hassan
Author: Raja Wasim Ahmad
Author: James Self ORCID iD
Author: Andrew H. Crosby
Author: Emma L. Baple
Author: Asma Gul

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