Hennekam syndrome can be caused by FAT4 mutations and be allelic to Van Maldergem syndrome

Hum Genet. 2014 Sep;133(9):1161-7. doi: 10.1007/s00439-014-1456-y. Epub 2014 Jun 7.


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.

Publication types

  • Comparative Study

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Alleles
  • Amino Acid Substitution
  • Cadherin Related Proteins
  • Cadherins / genetics*
  • Calcium-Binding Proteins / genetics*
  • Chromosome Mapping
  • Cohort Studies
  • Craniofacial Abnormalities / genetics*
  • Exome
  • Foot Deformities, Congenital / genetics*
  • Gene Library
  • Genetic Linkage
  • Genital Diseases, Male / genetics*
  • Genotype
  • Hand Deformities, Congenital / genetics*
  • Heterozygote
  • Homozygote
  • Humans
  • Intellectual Disability / genetics*
  • Joint Instability / genetics*
  • Lymphangiectasis, Intestinal / genetics*
  • Lymphedema / genetics*
  • Mutation
  • Pedigree
  • Phenotype
  • Sequence Analysis, RNA
  • Tumor Suppressor Proteins / genetics*


  • CCBE1 protein, human
  • CDHR6 protein, human
  • Cadherin Related Proteins
  • Cadherins
  • Calcium-Binding Proteins
  • FAT4 protein, human
  • Tumor Suppressor Proteins

Supplementary concepts

  • Hennekam lymphangiectasia lymphedema syndrome
  • Van Maldergem Wetzburger Verloes syndrome