Intrafamilial variability of ZRS-associated syndrome: characterization of a mosaic ZRS mutation by pyrosequencing.
During limb development, the spatio-temporal expression of sonic hedgehog (SHH) is driven by the Zone of polarizing activity Regulatory Sequence (ZRS), located 1 megabase upstream from SHH. Gain-of-function mutations of this enhancer, which cause ectopic expression of SHH, are known to be responsible for congenital limb malformations with variable expressivity, ranging from preaxial polydactyly or triphalangeal thumbs to polysyndactyly, which may also be associated with mesomelic deficiency. In this report, we describe a patient affected with mirror-image polydactyly of the four extremities and bilateral tibial deficiency. The proband's father had isolated preaxial polydactyly type II (PPD2). Using Sanger sequencing, a ZRS point mutation (NC_000007.14, g.156584153A>G, UCSC, Build hg.19) was only identified in the patient. However, pyrosequencing analysis enabled the detection of a 10% somatic mosaic in the blood and saliva from the father. To our knowledge, this is the first description of a ZRS mosaic mutation. This report highlights the complexity of genotype-phenotype correlation in ZRS-associated syndromes and the importance of detecting somatic mosaicism for accurate genetic counselling.
Institut de Biochimie et Génétique Moléculaire, Centre de Biologie Pathologie, CHRU, Lille, France.|Clinique de Génétique médicale, Hôpital Jeanne de Flandre, CHRU, Lille, France.|RADEME Research Team for Rare Metabolic and Developmental Diseases, Université Lille 2, Lille, France.
C
C
Vanlerberghe
Service de Génétique clinique, Hôpital d'enfants, Dijon, France.
L
L
Faivre
Clinique de Génétique médicale, Hôpital Jeanne de Flandre, CHRU, Lille, France.|RADEME Research Team for Rare Metabolic and Developmental Diseases, Université Lille 2, Lille, France.|Faculté de Médecine, Université Lille II, Lille, France.
F
F
Petit
Institut de Biochimie et Génétique Moléculaire, Centre de Biologie Pathologie, CHRU, Lille, France.|RADEME Research Team for Rare Metabolic and Developmental Diseases, Université Lille 2, Lille, France.
O
O
Fruchart
Institut de Biochimie et Génétique Moléculaire, Centre de Biologie Pathologie, CHRU, Lille, France.|RADEME Research Team for Rare Metabolic and Developmental Diseases, Université Lille 2, Lille, France.
A-S
AS
Jourdain
Centre de référence national maladies rares des malformations des membres et de l'arthrogrypose chez l'enfant Saint Maurice, Hôpital Saint Maurice, Saint Maurice, France.
F
F
Clavier
Service de pédiatrie, Centre Hospitalier William Morey, Chalon sur Saône, France.
S
S
Gay
Clinique de Génétique médicale, Hôpital Jeanne de Flandre, CHRU, Lille, France.|RADEME Research Team for Rare Metabolic and Developmental Diseases, Université Lille 2, Lille, France.|Faculté de Médecine, Université Lille II, Lille, France.
S
S
Manouvrier-Hanu
Institut de Biochimie et Génétique Moléculaire, Centre de Biologie Pathologie, CHRU, Lille, France.|RADEME Research Team for Rare Metabolic and Developmental Diseases, Université Lille 2, Lille, France.
F
F
Escande
D000015:Abnormalities, Multiple / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000013:Congenital Abnormalities / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D004480:Ectromelia / Q000235:genetics* / Q000378:metabolism; D005532:Foot Deformities, Congenital / Q000235:genetics* / Q000378:metabolism; D006228:Hand Deformities, Congenital / Q000235:genetics* / Q000378:metabolism; D053823:Hedgehog Proteins / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008342:Mandibulofacial Dysostosis / Q000235:genetics* / Q000378:metabolism; D009030:Mosaicism; D009297:Nasal Mucosa / Q000378:metabolism; D009666:Nose / Q000002:abnormalities*; D010375:Pedigree; D017354:Point Mutation
D053823:Hedgehog Proteins; C509239:SHH protein, human
ZRS; mirror-image polydactyly; pyrosequencing; somatic mosaicism; sonic hedgehog; tibial aplasia/hypoplasia