A syndromic form of Pierre Robin sequence is caused by 5q23 deletions encompassing FBN2 and PHAX.
Pierre Robin sequence (PRS) is an aetiologically distinct subgroup of cleft palate. We aimed to define the critical genomic interval from five different 5q22-5q31 deletions associated with PRS or PRS-associated features and assess each gene within the region as a candidate for the PRS component of the phenotype. Clinical array-based comparative genome hybridisation (aCGH) data were used to define a 2.08 Mb minimum region of overlap among four de novo deletions and one mother-son inherited deletion associated with at least one component of PRS. Commonly associated anomalies were talipes equinovarus (TEV), finger contractures and crumpled ear helices. Expression analysis of the orthologous genes within the PRS critical region in embryonic mice showed that the strongest candidate genes were FBN2 and PHAX. Targeted aCGH of the critical region and sequencing of these genes in a cohort of 25 PRS patients revealed no plausible disease-causing mutations. In conclusion, deletion of ∼2 Mb on 5q23 region causes a clinically recognisable subtype of PRS. Haploinsufficiency for FBN2 accounts for the digital and auricular features. A possible critical region for TEV is distinct and telomeric to the PRS region. The molecular basis of PRS in these cases remains undetermined but haploinsufficiency for PHAX is a plausible mechanism.
['Ansari|Morad|M|', 'Rainger|Jacqueline K|JK|', 'Murray|Jennie E|JE|', 'Hanson|Isabel|I|', 'Firth|Helen V|HV|', 'Mehendale|Felicity|F|', 'Amiel|Jeanne|J|', 'Gordon|Christopher T|CT|', 'Percesepe|Antonio|A|', 'Mazzanti|Laura|L|', 'Fryer|Alan|A|', 'Ferrari|Paola|P|', 'Devriendt|Koenraad|K|', 'Temple|I Karen|IK|', 'FitzPatrick|David R|DR|']
D000293:Adolescent D002648:Child D002895:Chromosomes, Human, Pair 5 D002972:Cleft Palate D003025:Clubfoot D003286:Contracture D004431:Ear, External D005260:Female D000071840:Fibrillin-2 D000071837:Fibrillins D005385:Fingers D017353:Gene Deletion D057895:Haploinsufficiency D006801:Humans D008297:Male D008840:Microfilament Proteins D020125:Mutation, Missense D029543:Nucleocytoplasmic Transport Proteins D010641:Phenotype D010750:Phosphoproteins D010855:Pierre Robin Syndrome D017384:Sequence Deletion D013577:Syndrome D055815:Young Adult
Pierre Robin sequence Talipes equinovarus 5q deletion Congenital contractural arachnodactyly Fibrillin 2 (FBN2) Phosphorylated adaptor for RNA export (PHAX)