Confirmation of TENM3 involvement in autosomal recessive colobomatous microphthalmia

Abstract

Anophthalmia and microphthalmia are the most severe malformations of the eye, referring to a congenital absence, and a reduced size of the eyeball respectively. More than 20 genes have been shown to be mutated in patients with syndromic and non-syndromic forms of anophthalmia-microphthalmia. In a recent study combining autozygome and exome analysis, a homozygous loss of function mutation in TENM3 (previously named ODZ3) was reported in two siblings with isolated bilateral colobomatous microphthalmia from a consanguineous Saudi family. Herein, we report a third patient (not related to the previously reported family) with bilateral colobomatous microphthalmia and developmental delay in whom genetic studies identified a homozygous TENM3 splicing mutation c.2968-2A>T (p.Val990Cysfs*13). This report supports the association of TENM3 mutations with colobomatous microphthalmia and expands the phenotypic spectrum associated with mutations in this gene. © 2016 Wiley Periodicals, Inc.

Genetic investigation of 93 families with microphthalmia or posterior microphthalmos

“…10 However, we note that C12orf57 is now a well-established cause of Temtamy syndrome in which microphthalmia is a prominent albeit inconsistent feature, and that an independent study has indeed validated ODZ3 as a microphthalmia candidate. 56 This supports the value of publishing novel candidate genes, as we do in this study, to facilitate their independent verification by the wider research community.…”

Novel truncating mutation in TENM3 in siblings with motor developmental delay, ocular coloboma, oval cornea, without microphthalmia

“…To the Editor, Your journal's recent article describes a second family with autosomal recessive colobomatous microphthalmia and developmental delay (Chassaing et al, 2016), supporting the association of TENM3 mutations with eye abnormalities, and further confirming the earlier report by Aldahmesh, Mohammed, Al-Hazzaa, and Alkuraya (2012). Coloboma refers to an ocular birth defect resulting from abnormal closure of the optic fissure during the fifth to seventh week of embryonic stage in humans (Nakamura, Diehl, & Mohney, 2011).…”

“…Odz3, the vertebrate orthologue of Teneurin transmembrane protein 3 encoded by human TENM3 gene, has been well studied for its role in axon guidance, homophilic cell adhesion, and ocular development (Ben-Zur, Feige, Motro, & Wides, 2000;Leamey et al, 2007). So far, four patients from three families manifested with microphthalmia been reported due to bi-allelic mutations in TENM3 (Aldahmesh et al, 2012;Chassaing et al, 2016;Singh, Srivastava, & Phadke, 2018). We now report a fourth family of Indian origin having novel truncating mutation in TENM3 in two similarly affected sisters who manifested with motor developmental delay, eye abnormalities, without microphthalmia.…”

High‐throughput custom capture sequencing identifies novel mutations in coloboma‐associated genes: Mutation in DNA‐binding domain of retinoic acid receptor beta affects nuclear localization causing ocular coloboma

“…Although several genes identified in animal studies are critical for optic fissure closure during eye development, very few are known to cause coloboma in humans (Brown et al, ; Patel & Sowden, ). On the other hand, reports of human mutations are often not complemented by experimental mechanistic evidence either in animal models or in cell culture (Bourchany et al, ; Chassaing et al, ; Graham et al, ; Kahrizi et al, ; Martinez‐Garay et al, ; Ng et al, ; Patel & Sowden, ; Wenger et al, ). In many cases, studies on coloboma genetics have focused on a select number of genes, and many have included syndromic conditions with severe ocular phenotypes (e.g., severe microphthalmia and anophthalmia; Gonzalez‐Rodriguez et al, ; Guo, Dai, Huang, Liao, & Bai, ; Mihelec et al, ; Morrison et al, ; Schimmenti et al, ; Williamson & FitzPatrick, ; X. Zhang et al, ; J. Zhou et al, ).…”