A syndromic form of Pierre Robin sequence is caused by 5q23 deletions encompassing FBN2 and PHAX

Abstract

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

A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD)

“…ALDH7A1 , encoding an acetaldehyde-oxidizing enzyme, is mutated in autosomal recessive pyridoxine-dependent epilepsy (OMIM#266100) ( 35 ). PHAX , encoding a protein identified in mouse as a component of the U snRNA export complex assembly, has recently been associated with the Pierre Robin Sequence ( 36 , 37 ). Although we cannot in principle rule out that these three genes play a role in ADLD-1-TO pathogenesis, it has to be noted that their experimentally induced simultaneous single-copy loss did not affect lamin B1 expression.…”

“…Cells were pelleted for 5 min (4600 G at 4°C), washed twice in 500 µl of 1× DpnII restriction buffer and re-suspended in 600 µl 1.2× DpnII restriction buffer. Restriction with DpnII, ligation, crosslink reversal and DNA purification were carried out as described previously ( 37 ).…”

Mosaic intragenic deletion of FBN2 and severe congenital contractural arachnodactyly

“…FBN2 variants leading to a premature termination codon are significantly underrepresented, with only one nonsense mutation reported . Recently, large deletions that include the FBN2 gene have been described in 5 unrelated patients who presented with a spectrum of clinical manifestations associated with CCA …”

Pierre Robin sequence with congenital talipes equinovarus

“…A possible region for CTEV is distinct and telomeric to the PRS region. There may be combined deletion of the region leading to simultaneous presentation 5 . Thus, the typical presentation like in our case goes in favour of gene deletion which may suggest a syndromic presentation of PRS with CTEV.…”