A Locus for Autosomal Dominant Colobomatous Microphthalmia Maps to Chromosome 15q12-q15

Abstract

Congenital microphthalmia is a common developmental ocular disorder characterized by shortened axial length. Isolated microphthalmia is clinically and genetically heterogeneous and may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. Here, we studied a five-generation family of Sephardic Jewish origin that included 38 members, of whom 7 have either unilateral or bilateral microphthalmia of variable severity inherited as an autosomal dominant trait with incomplete penetrance. After exclusion of several candidate loci, we performed a genome-scan study and demonstrated linkage to chromosome 15q12-q15. Positive LOD scores were obtained with a maximum at the D15S1007 locus (maximum LOD score 3.77, at recombination fraction 0.00). Haplotype analyses supported the location of the disease-causing gene in a 13.8-cM interval between loci D15S1002 and D15S1040.

Unilateral Autosomal Recessive Anophthalmia in a Patient with Cystic Craniopharyngioma

“…Three members of multiple generation family described by Fryns 9 had unilateral microphthalmia, whereas three other members suffered from bilateral anophthalmia. Five members of the family described by Morle et al 10 had anophthalmia/microphthalmia, whereas two had bilateral anophthalmia/microphthalmia. They also linked the autosomal dominant inheritance to chromosome 15q12-q15.…”

“…Nonsyndromic cases usually occur sporadically and are due to congenital infections, maternal teratogenic drug use, 4,14 and trauma. 15 Heredity has also been implicated to play a role in some of these sporadic non-syndromic cases of isolated anophthalmia and autosomal recessive, 4,8 autosomal dominant, 9,10 and X-linked inheritance 11 patterns have been described in literature. The inherited familial cases of anophthalmia usually have bilateral involvement.…”

“…Unilateral inherited anophthalmia has been reported only on few occasions. [8][9][10]16 Fryns 9 and Morle et al 10 described four-generation and five-generation families of anophthalmia/ microophthalmia, respectively, with autosomal dominant inheritance pattern with incomplete penetrance and variable expression. Three members of multiple generation family described by Fryns 9 had unilateral microphthalmia, whereas three other members suffered from bilateral anophthalmia.…”

Clinical utility gene card for: Non-Syndromic Microphthalmia Including Next-Generation Sequencing-Based Approaches

“…The occurrence of de novo mutations, mosaicism and incomplete penetrance makes prediction of the inheritance pattern difficult. Chromosomal duplications, deletions and translocations have been identified; a locus for autosomaldominant microphthalmia has been mapped to 15q12-15, 5 and for autosomal-recessive microphthalmia at 14q32. 6,7 Autosomal-recessive VSX2 variants (causing MCOP2) account for~2% of isolated microphthalmia cases, and are predominantly missense.…”

“…MCOPCB1 has been mapped to the X chromosome, 25 and MCOPCB2 to chromosome 15q12-q15. 26 Homozygosity for missense and a splice variant in VSX2 have been described in MCOPCB3 cases. 27,28 MCOPCB4 is isolated microphthalmia associated with colobomatous cyst and is transmitted as an autosomal-recessive trait.…”