Homozygosity Mapping and Targeted Sanger Sequencing Reveal Genetic Defects Underlying Inherited Retinal Disease in Families from Pakistan
March
Homozygosity Mapping and Targeted Sanger Sequencing Reveal Genetic Defects Underlying Inherited Retinal Disease in Families from Pakistan
Maleeha Maria 0 1
Muhammad Ajmal 0 1
Maleeha Azam 0 1
Nadia Khalida Waheed 0 1
Sorath Noorani Siddiqui 0 1
Bilal Mustafa 0 1
Humaira Ayub 0 1
Liaqat Ali 0 1
Shakeel Ahmad 0 1
Shazia Micheal 0 1
Alamdar Hussain 0 1
Syed Tahir Abbas Shah 0 1
Syeda Hafiza Benish Ali 0 1
Waqas Ahmed 0 1
Yar Muhammad Khan 0 1
Anneke I. den Hollander 0 1
Lonneke Haer- Wigman 0 1
Rob W. J. Collin 0 1
Muhammad Imran Khan 0 1
Raheel Qamar 0 1
Frans P. M. Cremers 0 1
0 1 Department of Biosciences, Commission on Science and Technology for Sustainable Development in the South Institute of Information Technology , Islamabad , Pakistan , 2 Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands, 3 Tufts University Medical School , Boston , Massachusetts, United States of America, 4 Al-Shifa Eye Trust Hospital , Rawalpindi , Pakistan , 5 Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands, 6 Institute of Pure and Applied Biology, Bahauddin Zakariya University , Multan , Pakistan , 7 University of Haripur, Haripur, Pakistan, 8 Department of Chemistry, University of Science and Technology , Bannu , Pakistan , 9 Radboud Institute for Molecular Life sciences, Radboud University Nijmegen, Nijmegen, the Netherlands, 10 Al- Nafees Medical College & Hospital, Isra University , Islamabad , Pakistan
1 Academic Editor: Tiansen Li, National Eye Institute, UNITED STATES
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Funding: This work was supported by grant no. PAS/
I-9/Project awarded to R.Q. and M.Az., by the
Pakistan Academy of Sciences, and a core grant
from the COMSATS Institute of Information
Technology (CIIT) to R.Q. This work was also
supported by CIIT grant No. 16-64/CRGP/CIIT/IBD/
12/919 awarded to M.M., grant No. 16-83/CRGP/
CIIT/IBD/13/144 awarded to M.Aj. and grant
No.1682-CRGP-CIIT-IBD-13/145 awarded to M.Az. This
work was also financially supported by the Stichting
Homozygosity mapping has facilitated the identification of the genetic causes underlying
inherited diseases, particularly in consanguineous families with multiple affected individuals.
This knowledge has also resulted in a mutation dataset that can be used in a cost and time
effective manner to screen frequent population-specific genetic variations associated with
diseases such as inherited retinal disease (IRD).
We genetically screened 13 families from a cohort of 81 Pakistani IRD families diagnosed
with Leber congenital amaurosis (LCA), retinitis pigmentosa (RP), congenital stationary
night blindness (CSNB), or cone dystrophy (CD). We employed genome-wide single
nucleotide polymorphism (SNP) array analysis to identify homozygous regions shared by
affected individuals and performed Sanger sequencing of IRD-associated genes located in the
sizeable homozygous regions. In addition, based on population specific mutation data we
Nederlands Oogheelkundig Onderzoek, the Nelly
Reef Foundation, the Stichting ter Verbetering van het
Lot der Blinden (to F.P.M.C., R.W.J.C., and A.I.d.H.),
the Gelderse Blinden Stichting (to F.P.M.C.), the
Rotterdamse Stichting Blindenbelangen, the Stichting
Blindenhulp, the Stichting A.F. Deutman
Researchfonds Oogheelkunde, and the Stichting voor
Ooglijders (to F.P.M.C. and M.I.K.). F.P.M.C. and M.I.
K. were also supported by the following foundations:
the Algemene Nederlandse Vereniging ter
Voorkoming van Blindheid, the Landelijke Stichting
voor Blinden en Slechtzienden, the Stichting Retina
Nederland Fonds, and the Novartis fund, contributed
through UitZicht. The work of L.H-W. was supported
by the Foundation Fighting Blindness USA
C-GE0811-0545-RAD01 (to F.P.M.C.). The funding
organizations provided unrestricted grants and had
no role in study design, data collection and analysis,
decision to publish, or preparation of the manuscript.
performed targeted Sanger sequencing (TSS) of frequent variants in AIPL1, CEP290,
CRB1, GUCY2D, LCA5, RPGRIP1 and TULP1, in probands from 28 LCA families.
Homozygosity mapping and Sanger sequencing of IRD-associated genes revealed the
underlying mutations in 10 families. TSS revealed causative variants in three families. In these
13 families four novel mutations were identified in CNGA1, CNGB1, GUCY2D, and RPGRIP1.
Homozygosity mapping and TSS revealed the underlying genetic cause in 13 IRD families,
which is useful for genetic counseling as well as therapeutic interventions that are likely to
become available in the near future.
Inherited retinal diseases (IRD) refer to a clinically and genetically heterogeneous group of
genetic eye disorders in which the photoreceptors and retinal pigment epithelium can be affected.
There is an overlap of clinical features between different IRDs, which includes syndromic or
non-syndromic conditions. In cone dystrophy (CD), only central vision is impaired, whereas
in cone-rod dystrophy (CRD) peripheral vision (...truncated)