Clinical and mutation analysis of 51 probands with anophthalmia and/or severe microphthalmia from a single center.
Clinical evaluation and mutation analysis was performed in 51 consecutive probands with severe eye malformations - anophthalmia and/or severe microphthalmia - seen in a single specialist ophthalmology center. The mutation analysis consisted of bidirectional sequencing of the coding regions of SOX2, OTX2, PAX6 (paired domain), STRA6, BMP4, SMOC1, FOXE3, and RAX, and genome-wide array-based copy number assessment. Fifteen (29.4%) of the 51 probands had likely causative mutations affecting SOX2 (9/51), OTX2 (5/51), and STRA6 (1/51). Of the cases with bilateral anophthalmia, 9/12 (75%) were found to be mutation positive. Three of these mutations were large genomic deletions encompassing SOX2 (one case) or OTX2 (two cases). Familial inheritance of three intragenic, plausibly pathogenic, and heterozygous mutations was observed. An unaffected carrier parent of an affected child with an identified OTX2 mutation confirmed the previously reported nonpenetrance for this disorder. Two families with SOX2 mutations demonstrated a parent and child both with significant but highly variable eye malformations. Heterozygous loss-of-function mutations in SOX2 and OTX2 are the most common genetic pathology associated with severe eye malformations and bi-allelic loss-of-function in STRA6 is confirmed as an emerging cause of nonsyndromal eye malformations.
Department of Ophthalmology, University of Rostock Germany.
Christina
C
Gerth-Kahlert
MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Western General Hospital Edinburgh, EH4 2XU, United Kingdom.
Kathleen
K
Williamson
MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Western General Hospital Edinburgh, EH4 2XU, United Kingdom.
Morad
M
Ansari
MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Western General Hospital Edinburgh, EH4 2XU, United Kingdom.
Jacqueline K
JK
Rainger
Department of Radiology, University of Rostock Germany.
Volker
V
Hingst
Department of Pediatrics, University of Erlangen Germany.
Theodor
T
Zimmermann
Department of Ophthalmology, University of Rostock Germany.
Stefani
S
Tech
Department of Ophthalmology, University of Rostock Germany.
Rudolf F
RF
Guthoff
MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Western General Hospital Edinburgh, EH4 2XU, United Kingdom.
Veronica
V
van Heyningen
MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Western General Hospital Edinburgh, EH4 2XU, United Kingdom.
David R
DR
Fitzpatrick
Anophthalmia; BMP4; FOXE3; OTX2; PAX6; RAX; SMOC1; SOX2; STRA6; array CGH; coloboma; de novo mutations; gene deletion; haploinsufficiency; microphthalmia; missense mutations; transcription factors