TY - JOUR
T1 - Molecular genetic analysis of pakistani families with autosomal recessive congenital cataracts by homozygosity screening
AU - Chen, Jianjun
AU - Wang, Qiwei
AU - Cabrera, Patricia E.
AU - Zhong, Zilin
AU - Sun, Wenmin
AU - Jiao, Xiaodong
AU - Chen, Yabin
AU - Govindarajan, Gowthaman
AU - Naeem, Muhammad Asif
AU - Khan, Shaheen N.
AU - Ali, Muhammad Hassaan
AU - Assir, Muhammad Zaman
AU - Rahman, Fawad Ur
AU - Qazi, Zaheeruddin A.
AU - Riazuddin, Sheikh
AU - Akram, Javed
AU - Riazuddin, S. Amer
AU - Hejtmancik, J. Fielding
N1 - Publisher Copyright:
© 2017 The Authors.
PY - 2017/4
Y1 - 2017/4
N2 - PURPOSE. To identify the genetic origins of autosomal recessive congenital cataracts (arCC) in the Pakistani population. METHODS. Based on the hypothesis that most arCC patients in consanguineous families in the Punjab areas of Pakistan should be homozygous for causative mutations, affected individuals were screened for homozygosity of nearby highly informative microsatellite markers and then screened for pathogenic mutations by DNA sequencing. A total of 83 unmapped consanguineous families were screened for mutations in 33 known candidate genes. RESULTS. Patients in 32 arCC families were homozygous for markers near at least 1 of the 33 known CC genes. Sequencing the included genes revealed homozygous cosegregating sequence changes in 10 families, 2 of which had the same variation. These included five missense, one nonsense, two frame shift, and one splice site mutations, eight of which were novel, in EPHA2, FOXE3, FYCO1, TDRD7, MIP, GALK1, and CRYBA4. CONCLUSIONS. The above results confirm the usefulness of homozygosity mapping for identifying genetic defects underlying autosomal recessive disorders in consanguineous families. In our ongoing study of arCC in Pakistan, including 83 arCC families that underwent homozygosity mapping, 3 mapped using genome-wide linkage analysis in unpublished data, and 30 previously reported families, mutations were detected in approximately 37.1% (43/ 116) of all families studied, suggesting that additional genes might be responsible in the remaining families. The most commonly mutated gene was FYCO1 (14%), followed by CRYBB3 (5.2%), GALK1 (3.5%), and EPHA2 (2.6%). This provides the first comprehensive description of the genetic architecture of arCC in the Pakistani population.
AB - PURPOSE. To identify the genetic origins of autosomal recessive congenital cataracts (arCC) in the Pakistani population. METHODS. Based on the hypothesis that most arCC patients in consanguineous families in the Punjab areas of Pakistan should be homozygous for causative mutations, affected individuals were screened for homozygosity of nearby highly informative microsatellite markers and then screened for pathogenic mutations by DNA sequencing. A total of 83 unmapped consanguineous families were screened for mutations in 33 known candidate genes. RESULTS. Patients in 32 arCC families were homozygous for markers near at least 1 of the 33 known CC genes. Sequencing the included genes revealed homozygous cosegregating sequence changes in 10 families, 2 of which had the same variation. These included five missense, one nonsense, two frame shift, and one splice site mutations, eight of which were novel, in EPHA2, FOXE3, FYCO1, TDRD7, MIP, GALK1, and CRYBA4. CONCLUSIONS. The above results confirm the usefulness of homozygosity mapping for identifying genetic defects underlying autosomal recessive disorders in consanguineous families. In our ongoing study of arCC in Pakistan, including 83 arCC families that underwent homozygosity mapping, 3 mapped using genome-wide linkage analysis in unpublished data, and 30 previously reported families, mutations were detected in approximately 37.1% (43/ 116) of all families studied, suggesting that additional genes might be responsible in the remaining families. The most commonly mutated gene was FYCO1 (14%), followed by CRYBB3 (5.2%), GALK1 (3.5%), and EPHA2 (2.6%). This provides the first comprehensive description of the genetic architecture of arCC in the Pakistani population.
KW - Autosomal recessive congenital cataracts
KW - Consanguineous
KW - Genetic analysis
KW - Homozygosity mapping
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U2 - 10.1167/iovs.17-21469
DO - 10.1167/iovs.17-21469
M3 - Article
C2 - 28418495
AN - SCOPUS:85018505086
SN - 0146-0404
VL - 58
SP - 2207
EP - 2217
JO - Investigative Ophthalmology and Visual Science
JF - Investigative Ophthalmology and Visual Science
IS - 4
ER -