Clinical and mutation analysis of 51 probands with anophthalmia and/or severe microphthalmia from a single center

Abstract

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.

Novel splice-site and missense mutations in theALDH1A3gene underlying autosomal recessive anophthalmia/microphthalmia

“…It was suggested that a screen for heterozygous SOX2 and OTX2 mutations should be the first-line test in isolated cases with A/M 34. Regarding the autosomal recessive form of this malformation, a total of five genes ( MFRP [MIM 606227] , PRSS56 [MIM 613858] , RAX [MIM 601881] , CHX10 [MIM 142993] , STRA6 [MIM 610745]) have been associated with this malformation, to which ALDH1A3 (MIM 600463) is added.…”

The zebrafish eye—a paradigm for investigating human ocular genetics

“…Although the aetiology of microphthalmia/anophthalmia is complex, heterozygous loss-of-function mutations in SOX2 or OTX2 have been described as the most prevalent monogenic cause to date. 26 Microphthalmia-causing mutations have also been described in CHX10, OTX2, PAX6, RAX, BMP4, GDF6, and GDF3.…”

Sunitinib Treatment Exacerbates Intratumoral Heterogeneity in Metastatic Renal Cancer

“…Samples were fragmented before proteinase K digestion using a Qiagen Tissue Lyser. aCGH hybridization was carried out as described previously (8).…”