Adams-Oliver Syndrome 4

A number sign (#) is used with this entry because of evidence that autosomal recessive Adams-Oliver syndrome-4 (AOS4) can be caused by homozygous mutation in the EOGT gene (614789) on chromosome 3p14.

Description

Adams-Oliver syndrome is a rare congenital disorder characterized by aplasia cutis congenita and terminal transverse limb defects. Additional abnormalities may be present in other organs, e.g., heart, brain, and/or eyes (summary by Shaheen et al., 2013).

For a discussion of genetic heterogeneity of Adams-Oliver syndrome (AOS), see AOS1 (100300).

Clinical Features

Shaheen et al. (2013) studied 5 affected children from 3 consanguineous Arab families who had Adams-Oliver syndrome. All patients displayed typical features of AOS, including cutis aplasia of the scalp and terminal transverse digit defects of the feet, with hypoplastic or absent nails and variably absent distal phalanges. The probands from 2 families also had cardiac defects, including an atrial and a ventricular septal defect and patent ductus arteriosus that resolved; the 3 affected individuals from the third family had no cardiac defects, and none of the 5 patients exhibited microphthalmia.

Mapping

In affected members of 3 consanguineous Arab families with Adams-Oliver syndrome in whom no mutation in the DOCK6 gene (614194) was detected, Shaheen et al. (2013) found autozygome overlap on a previously unreported 2,744,933-bp locus at Chr3:66,612,406-69,357,338 (GRCh37). Linkage analysis confirmed the locus, with a single peak that corresponded to the same critical region of homozygosity highlighted by autozygome analysis, yielding a lod score of approximately 3.7.

Molecular Genetics

In a 5-week-old girl from a consanguineous Arab family with AOS mapping to chromosome 3, Shaheen et al. (2013) performed exome sequencing and identified a homozygous missense mutation in the EOGT gene (W207S; 614789.0001), located within the critical locus. Sanger sequencing confirmed the homozygous mutation in the proband and showed that her unaffected parents were heterozygous carriers of the mutation. Screening of EOGT in 4 affected members from 2 more consanguineous Arab families revealed homozygosity for a 1-bp deletion (614789.0002) and for a missense mutation (R377Q; 614789.0003) that segregated with disease in both families, respectively. None of the variants were found in 230 Saudi exomes, the 1000 Genomes Project, or the NHLBI Exome Variant Server.