title: Genetic analysis of consanguineous families presenting with congenital ocular defects.
abstract: Anophthalmia and microphthalmia (A/M) are a group of rare developmental disorders that affect the size of the ocular globe. A/M may present as the sole clinical feature, but are also frequently found in a variety of syndromes. A/M is genetically heterogeneous and can be caused by chromosomal aberrations, copy number variations and single gene mutations. To date, A/M has been caused by mutations in at least 20 genes that show different modes of inheritance. In this study, we enrolled eight consanguineous families with A/M, including seven from Pakistan and one from India. Sanger and exome sequencing of DNA samples from these families identified three novel mutations including two mutations in the Aldehyde Dehydrogenase 1 Family Member A3 (ALDH1A3) gene, [c.1310_1311delAT; p.(Tyr437Trpfs*44) and c.964G > A; p.(Val322Met)] and a single missense mutation in Forkhead Box E3 (FOXE3) gene, [c.289A > G p.(Ile97Val)]. Additionally two previously reported mutations were identified in FOXE3 and in Visual System Homeobox 2 (VSX2). This is the first comprehensive study on families with A/M from the Indian subcontinent which provides further evidence for the involvement of known genes with novel and recurrent mutations.
authors.affiliation: Department of Biochemistry, Quaid-i-Azam University, Islamabad, 45320, Pakistan; Department of Pediatrics, University of California, San Francisco, CA, USA.
authors.forename: Ehsan
authors.initials: E
authors.lastname: Ullah
authors.affiliation: Department of Biochemistry, Quaid-i-Azam University, Islamabad, 45320, Pakistan; Pakistan Medical Research Council, Islamabad, Pakistan.
authors.forename: Muhammad Arif
authors.initials: MA
authors.lastname: Nadeem Saqib
authors.affiliation: Department of Biochemistry, Quaid-i-Azam University, Islamabad, 45320, Pakistan.
authors.forename: Sundus
authors.initials: S
authors.lastname: Sajid
authors.affiliation: Department of Biochemistry, Quaid-i-Azam University, Islamabad, 45320, Pakistan.
authors.forename: Neelam
authors.initials: N
authors.lastname: Shah
authors.affiliation: Gomal Centre of Biochemistry and Biotechnology, Gomal University, Dera Ismail Khan, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Zubair
authors.affiliation: Gomal Centre of Biochemistry and Biotechnology, Gomal University, Dera Ismail Khan, Pakistan; Genomic Core Facility, Interim Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.
authors.forename: Muzammil Ahmad
authors.initials: MA
authors.lastname: Khan
authors.affiliation: Department of Community Medicine, Gomal Medical College, Dera Ismail Khan, Khyber- Pakhtoonkhuwa, Pakistan.
authors.forename: Iftikhar
authors.initials: I
authors.lastname: Ahmed
authors.affiliation: Department of Biotechnology, University of Azad Jammu and Kashmir, Muzaffarabad, Azad Jammu & Kashmir, Pakistan.
authors.forename: Ghazanfar
authors.initials: G
authors.lastname: Ali
authors.affiliation: Medical Genetics Unit, Christian Medical College, Vellore, India.
authors.forename: Atanu Kumar
authors.initials: AK
authors.lastname: Dutta
authors.affiliation: Medical Genetics Unit, Christian Medical College, Vellore, India.
authors.forename: Sumita
authors.initials: S
authors.lastname: Danda
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Lao
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Ling-Fung Tang
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
authors.forename: Pui-Yan
authors.initials: PY
authors.lastname: Kwok
authors.affiliation: Department of Biochemistry, Quaid-i-Azam University, Islamabad, 45320, Pakistan. Electronic address: ansar@qau.edu.pk.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ansar
authors.affiliation: Department of Pediatrics, University of California, San Francisco, CA, USA. Electronic address: slavotia@peds.ucsf.edu.
authors.forename: Anne
authors.initials: A
authors.lastname: Slavotinek
mesh_terms: D000293:Adolescent; D000853:Anophthalmos / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics*; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics; D005190:Family; D005260:Female; D005820:Genetic Testing; D006801:Humans; D007194:India / Q000453:epidemiology; D007223:Infant; D008297:Male; D008850:Microphthalmos / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D009154:Mutation; D010154:Pakistan / Q000453:epidemiology; D010375:Pedigree
chemical_list: D004247:DNA
keywords: ALDH1A3; Anophthalmia; Autosomal recessive; Consanguinity; FOXE3; Microphthalmia; VSX2; Whole exome sequencing