title: Hennekam syndrome can be caused by FAT4 mutations and be allelic to Van Maldergem syndrome.
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.
authors.affiliation: Department of Clinical Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands.
authors.forename: Mariëlle
authors.initials: M
authors.lastname: Alders
authors.forename: Lihadh
authors.initials: L
authors.lastname: Al-Gazali
authors.forename: Isabelle
authors.initials: I
authors.lastname: Cordeiro
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.forename: Livia
authors.initials: L
authors.lastname: Garavelli
authors.forename: Beyhan
authors.initials: B
authors.lastname: Tuysuz
authors.forename: Faranak
authors.initials: F
authors.lastname: Salehi
authors.forename: Martin A
authors.initials: MA
authors.lastname: Haagmans
authors.forename: Olaf R
authors.initials: OR
authors.lastname: Mook
authors.forename: Charles B
authors.initials: CB
authors.lastname: Majoie
authors.forename: Marcel M
authors.initials: MM
authors.lastname: Mannens
authors.forename: Raoul C
authors.initials: RC
authors.lastname: Hennekam
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000483:Alleles; D019943:Amino Acid Substitution; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000235:genetics*; D002874:Chromosome Mapping; D015331:Cohort Studies; D019465:Craniofacial Abnormalities / Q000235:genetics*; D059472:Exome; D005532:Foot Deformities, Congenital / Q000235:genetics*; D015723:Gene Library; D008040:Genetic Linkage; D005832:Genital Diseases, Male / Q000235:genetics*; D005838:Genotype; D006228:Hand Deformities, Congenital / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D007593:Joint Instability / Q000235:genetics*; D008201:Lymphangiectasis, Intestinal / Q000235:genetics*; D008209:Lymphedema / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D017423:Sequence Analysis, RNA; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D000070585:Cadherin Related Proteins; D015820:Cadherins; D002135:Calcium-Binding Proteins; D025521:Tumor Suppressor Proteins; C546964:CCBE1 protein, human; C442479:DCHS1 protein, human; C534294:FAT4 protein, human