ABSTRACT
The Hennekam lymphangiectasia-lymphedema syndrome is a genetically heterogeneous disorder. It can be caused by mutations in CCBE1 which are found in approximately 25 % of cases. We used homozygosity mapping and whole-exome sequencing in the original HS family with multiple affected individuals in whom no CCBE1 mutation had been detected, and identified a homozygous mutation in the FAT4 gene. Subsequent targeted mutation analysis of FAT4 in a cohort of 24 CCBE1 mutation-negative Hennekam syndrome patients identified homozygous or compound heterozygous mutations in four additional families. Mutations in FAT4 have been previously associated with Van Maldergem syndrome. Detailed clinical comparison between van Maldergem syndrome and Hennekam syndrome patients shows that there is a substantial overlap in phenotype, especially in facial appearance. We conclude that Hennekam syndrome can be caused by mutations in FAT4 and be allelic to Van Maldergem syndrome.
Subject(s)
Abnormalities, Multiple/genetics , Cadherins/genetics , Calcium-Binding Proteins/genetics , Craniofacial Abnormalities/genetics , Foot Deformities, Congenital/genetics , Genital Diseases, Male/genetics , Hand Deformities, Congenital/genetics , Intellectual Disability/genetics , Joint Instability/genetics , Lymphangiectasis, Intestinal/genetics , Lymphedema/genetics , Tumor Suppressor Proteins/genetics , Alleles , Amino Acid Substitution , Cadherin Related Proteins , Chromosome Mapping , Cohort Studies , Exome , Gene Library , Genetic Linkage , Genotype , Heterozygote , Homozygote , Humans , Mutation , Pedigree , Phenotype , Sequence Analysis, RNAABSTRACT
Lymphedema, lymphangiectasias, mental retardation and unusual facial characteristics define the autosomal recessive Hennekam syndrome. Homozygosity mapping identified a critical chromosomal region containing CCBE1, the human ortholog of a gene essential for lymphangiogenesis in zebrafish. Homozygous and compound heterozygous mutations in seven subjects paired with functional analysis in a zebrafish model identify CCBE1 as one of few genes causing primary generalized lymph-vessel dysplasia in humans.
