title: NEK1 and DYNC2H1 are both involved in short rib polydactyly Majewski type but not in Beemer Langer cases.
abstract: BACKGROUND
  The lethal short rib polydactyly syndromes (SRP type I-IV) are characterised by notably short ribs, short limbs, polydactyly, multiple anomalies of major organs, and autosomal recessive mode of inheritance. Among them, SRP type II (Majewski; MIM 263520) is characterised by short ovoid tibiae or tibial agenesis and is radiographically closely related to SRP type IV (Beemer-Langer; MIM 269860) which is distinguished by bowed radii and ulnae and relatively well tubulated tibiae. NEK1 mutations have been recently identified in SRP type II. Double heterozygosity for mutations in both NEK1 and DYNC2H1 in one SRP type II case supported possible digenic diallelic inheritance.
  
  
  METHODS
  The aim of this study was to screen DYNC2H1 and NEK1 in 13 SRP type II cases and seven SRP type IV cases. It was not possible to screen DYNC2H1 in two patients due to insufficient amount of DNA.
  
  
  RESULTS
  The study identified homozygous NEK1 mutations in 5/13 SRP type II and compound heterozygous DYNC2H1 mutations in 4/12 cases. Finally, NEK1 and DYNC2H1 were excluded in 3/12 SRP type II and in all SRP type IV cases. The main difference between the mutation positive SRP type II group and the mutation negative SRP type II group was the presence of holoprosencephaly and polymycrogyria in the mutation negative group.
  
  
  CONCLUSIONS
  This study confirms that NEK1 is one gene causing SRP type II but also reports mutations in DYNC2H1, expanding the phenotypic spectrum of DYNC2H1 mutations. The exclusion of NEK1 and DYNC2H1 in 3/12 SRP type II and in all SRP type IV cases further support genetic heterogeneity.
authors.affiliation: Department of Genetics, INSERM U781, Hôpital Necker, Université Paris Descartes, Sorbonne Paris Cité, Paris 75015, France.
authors.forename: Joyce
authors.initials: J
authors.lastname: El Hokayem
authors.forename: Céline
authors.initials: C
authors.lastname: Huber
authors.forename: Adeline
authors.initials: A
authors.lastname: Couvé
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Aziza
authors.forename: Geneviève
authors.initials: G
authors.lastname: Baujat
authors.forename: Raymonde
authors.initials: R
authors.lastname: Bouvier
authors.forename: Denise P
authors.initials: DP
authors.lastname: Cavalcanti
authors.forename: Felicity A
authors.initials: FA
authors.lastname: Collins
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Cordier
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Delezoide
authors.forename: Marie
authors.initials: M
authors.lastname: Gonzales
authors.forename: Diana
authors.initials: D
authors.lastname: Johnson
authors.forename: Martine
authors.initials: M
authors.lastname: Le Merrer
authors.forename: Annie
authors.initials: A
authors.lastname: Levy-Mozziconacci
authors.forename: Philippe
authors.initials: P
authors.lastname: Loget
authors.forename: Dominique
authors.initials: D
authors.lastname: Martin-Coignard
authors.forename: Jelena
authors.initials: J
authors.lastname: Martinovic
authors.forename: Geert R
authors.initials: GR
authors.lastname: Mortier
authors.forename: Marie-José
authors.initials: MJ
authors.lastname: Perez
authors.forename: Joëlle
authors.initials: J
authors.lastname: Roume
authors.forename: Gioacchino
authors.initials: G
authors.lastname: Scarano
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics*; D003241:Consanguinity; D056445:Cytoplasmic Dyneins / Q000235:genetics*; D005260:Female; D005333:Fetus / Q000002:abnormalities; D056726:Genetic Association Studies; D018740:Genetic Heterogeneity; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D000072380:NIMA-Related Kinase 1; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012779:Short Rib-Polydactyly Syndrome / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; C099883:DYNC2H1 protein, human; C000606914:NEK1 protein, human; D000072380:NIMA-Related Kinase 1; D017346:Protein Serine-Threonine Kinases; D056445:Cytoplasmic Dyneins