Genetic heterogeneity of syndromic X‐linked recessive microphthalmia‐anophthalmia: Is Lenz microphthalmia a single disorder?

Abstract

Nonsyndromic congenital microphthalmia or anophthalmia is a heterogeneous malformation with autosomal dominant, autosomal recessive, and X-linked modes of inheritance. Lenz microphthalmia syndrome comprises microphthalmia with mental retardation, malformed ears, skeletal anomalies, and is inherited in an X-linked recessive pattern. Prior studies have shown linkage of both isolated (or nonsyndromic) anophthalmos (ANOP1, [MIM 301590]) and Lenz syndrome [MIM 309800] to Xq27-q28. Nonsyndromic colobomatous microphthalmia [MIM 300345] has been linked to Xp11.4-Xq11.1. We describe a five-generation African-American family with microphthalmia or anophthalmia, mental retardation, and urogenital anomalies, in an X-linked recessive inheritance pattern, consistent with Lenz syndrome. Initial linkage analysis with microsatellite markers excluded the region in Xq27-q28 previously reported as a candidate region for ANOP1 [MIM 301590]. An X-chromosome scan revealed linkage to a 10-cM region between markers DXS228 and DXS992 in Xp11.4-p21.2. Multipoint analysis gave a maximum LOD score of 2.46 at marker DXS993. These data show that X-linked recessive syndromic microphthalmia exhibits genetic heterogeneity. In addition, it suggests that Lenz microphthalmia syndrome, previously thought to be a single disorder, may represent an amalgam of two distinct disorders.

Characterization of Bcor expression in mouse development

“…Another form of MCOPS2, which is distinct from OFCD, occurs in males with a single missense mutation (p.P85L) in the fourth coding exon of BCOR (Horn et al, 2005;Ng et al, 2004). In the described family, this syndrome is inherited in an X-linked recessive pattern and comprises microphthalmia/anophthalmia, mental retardation, and skeletal and other anomalies (Ng et al, 2002). RNAi knock-down of Bcor in zebrafish results in eye, skeletal and nervous system abnormalities consistent with those found in MCOPS2 patients (Ng et al, 2004).…”

Oculofaciocardiodental and Lenz microphthalmia syndromes result from distinct classes of mutations in BCOR

“…We sequenced the remaining 11 genes in members of the family in which MAA2 was originally identified. Ten of these genes showed no alterations, but we identified a missense change (nt 254C→T) in BCOR 4 that co-segregated with the disease phenotype (lod score of 2.46, above the threshold of 2.0 for X linkage 3 ). The corresponding residue of human BCOR, Pro85, is conserved in mouse, rat, chicken and pufferfish (Fig.…”

“…We had previously localized MAA2 to a 10-Mb candidate region of Xp 3 . To identify the gene, we narrowed this region by excluding regions deleted in males with Xp deletions but without microphthalmia.…”

“…2 Academic Unit of Medical Genetics and Regional Genetic Service, St Mary's Hospital, Manchester, UK. 3 Department of Genetics, Cell Biology and Development and Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA. 4 Department of Genetics, Albert Einstein Medical Center, Philadelphia, Pennsylvania, USA.…”

Novel mutations in BCOR in three patients with oculo-facio-cardio-dental syndrome, but none in Lenz microphthalmia syndrome

“…Two genetic loci that can cause what is currently considered to be Lenz microphthalmia syndrome have been reported, one located in Xq27 -q28 (MAA) 4 and the second in Xp11.4 -p21.2 (MAA2). 5 A single missense change, c.254C4T…”