Coloboma, Ocular, With Or Without Hearing Impairment, Cleft Lip/palate, And/or Mental Retardation

A number sign (#) is used with this entry because of evidence that ocular coloboma with or without hearing impairment, cleft lip/palate, and/or mental retardation (COB1) is caused by heterozygous mutation in the YAP1 gene (606608) on chromosome 11q22.

Clinical Features

Collum (1971) described uveal colobomata with other anomalies in 3 generations of a family. The features, both ocular and nonocular, were variable, but uveal coloboma was the most consistent feature. Kingston et al. (1982) studied the same family and concluded that cleft lip/palate and mental retardation of variable degree were manifestations of the same single gene defect. The affected members of the family were described as having typical iris coloboma with involvement of the choroid or extending to the disc and macula. Whereas 11 members had uveal coloboma, 4 of the 11 had cleft lip and palate. In an addendum, the authors noted the birth of another affected baby with bilateral cleft lip/palate and bilateral severe microphthalmia.

Ravine et al. (1997) restudied the family that was originally reported by Collum (1971). There were affected individuals in 4 generations. Wide variability in expression was evident. Additional manifestations included a complete spectrum of eye involvement, including iris and chorioretinal coloboma, microphthalmia, cataract, and impairment of extraocular movement, as well as mid-frequency sensorineural hearing loss, and hematuria. Learning disabilities requiring remedial teaching were present in one third of the affected persons, and a neural tube defect had occurred in 1 presumably affected member. No male-to-male transmission was noted in the family. Indeed, in the first 3 generations, there were only 2 affected males and neither had children.

Molecular Genetics

In an affected uncle-niece pair with isolated bilateral ocular coloboma, Williamson et al. (2014) performed whole-exome sequencing and did not detect any variants in known genes associated with eye malformations, but did identify heterozygosity for a nonsense mutation in the YAP1 gene (R124X; 606608.0001) that was also present in 2 more affected family members. The mutation was inherited from the unaffected grandfather in whom the mutation was apparently nonpenetrant; mosaicism was not evident in peripheral blood-derived DNA, and no other tissues were available from the grandfather. In a separate exome sequencing study involving 10 unrelated individuals with severe bilateral eye malformations, another missense mutation in YAP1 (E356X; 606608.0002) was identified in an affected member of the family with syndromic ocular coloboma originally described by Collum (1971). All 13 affected family members available for testing carried the E356X mutation, yielding a maximum lod score of 3.3; the combined lod score for the segregation of the nonsense mutations in both families was 4.2. Noting that there is an alternative transcription start site (TSS) in intron 1 of the YAP1 gene and that the R124X mutation is located in the 5-prime untranslated region of the alternative transcript, Williamson et al. (2014) proposed that partial rescue by transcripts from the alternative TSS in the family with the R124X mutation might explain their more restricted phenotype.