Microphthalmia, Syndromic 12
A number sign (#) is used with this entry because of evidence that syndromic microphthalmia-12 (MCOPS12) is caused by compound heterozygous or heterozygous mutation in the RARB gene (180220) on chromosome 3p24.
MCOPS9 (601186), in which patients exhibit a similar constellation of features, is caused by mutation in the STRA6 gene (610745).
Clinical FeaturesChitayat et al. (2007) described 3 deceased sibs, born to nonconsanguineous parents of French Canadian and English descent, with bilateral microphthalmia, pulmonary hypoplasia, and diaphragmatic hernia, who also exhibited mild facial dysmorphism with broad nasal root and tip and micrognathia. The female infant also had a small bicornuate uterus and cleft palate, and 1 of the male sibs had unfixed malrotated bowel. An earlier pregnancy had resulted in death due to presumed tangled cord, but was strongly suspected to represent the same syndrome. Chitayat et al. (2007) also reported an unrelated living child, a 9.5-year-old boy born to nonconsanguineous French parents, who had bilateral severe microphthalmia and underwent repair of a left diaphragmatic hernia at 2 months of age; lung CT scan did not show pulmonary hypoplasia, and pulmonary function tests at 19 months of age showed normal lung capacity. Dysmorphic features included sparse hair, brachycephaly, deep-set orbits, short palpebral fissures, and flat nasal bridge. He had severe language delay and was wheelchair-bound due to truncal hypotonia with spastic tetraparesis.
Molecular GeneticsIn a nonconsanguineous family with 4 microphthalmic sibs who had variable additional features, including diaphragmatic hernia, pulmonary hypoplasia, and cardiac abnormalities, who were originally reported by Chitayat et al. (2007) and found to be negative for mutation in the STRA6 gene, Srour et al. (2013) performed whole-exome sequencing and identified compound heterozygosity for a nonsense mutation (R119X; 180220.0001) and a 2-bp insertion (180220.0002) in the RARB gene. The unaffected parents were each heterozygous for 1 of the mutations, and neither was found in an unaffected sister. Analysis of the RARB gene in 15 patients with unilateral or bilateral clinical anophthalmia or microphthalmia who also had at least 1 abnormality involving the diaphragm, heart, or lung, in whom mutation in the STRA6 gene had been excluded by Chassaing et al. (2013), revealed 3 unrelated individuals who were heterozygous for de novo missense mutations at the same nucleotide (R387C, 180220.0003; R387S, 180220.0004). One of these 3 was the only living patient from the report of Chitayat et al. (2007). None of the mutations was found in more than 1,000 exomes or in the 1000 Genomes Project, Exome Variant Server, or dbSNP (build 138) databases.
Exclusion Studies
Chitayat et al. (2007) sequenced the STRA6 gene (610745) in a 9.5-year-old boy and in 1 of 3 sibs with microphthalmia, pulmonary hypoplasia, and diaphragmatic hernia, but did not detect any mutations.