Findings from aCGH in patients with congenital diaphragmatic hernia (CDH): A possible locus for Fryns syndrome

S Kantarci,S Manning,V Kimonis,R Jennings,J.P Fryns,P.K Donahoe,D Casavant,L.B Holmes,T.K Boyd,C Prada,B.R Pober,M Russell,J Byrne,L Wilkins Haug,C Lee

doi:10.1002/ajmg.a.31025

Abstract

Congenital diaphragmatic hernia (CDH) is a common and often devastating birth defect that can occur in isolation or as part of a malformation complex. Considerable progress is being made in the identification of genetic causes of CDH. We applied array-based comparative genomic hybridization (aCGH) of approximately 1Mb resolution to 29 CDH patients with prior normal karyotypes who had been recruited into our multi-site study. One patient, clinically diagnosed with Fryns syndrome, demonstrated a de novo 5Mb deletion at chromosome region 1q41-q42.12 that was confirmed by FISH. Given prior reports of CDH in association with cytogenetic abnormalities in this region, we propose that this represents a locus for Fryns syndrome, a Fryns syndrome phenocopy, or CDH.

Highlights

Congenital diaphragmatic hernia (CDH) refers to a group of common developmental defects in the formation of the diaphragm [Tibboel and Gaag, 1996] found in as many as 1/3,000 live births
Discussion array-based comparative genomic hybridization (aCGH) is a powerful tool for detecting genomic imbalances at a high resolution and has been used increasingly to uncover abnormalities in patients with structural birth defects, dysmorphology, and learning disabilities or mental retardation
Evaluations of such patients, who had prior normal karyotypes, demonstrate a 10-15% frequency of de novo deletions or duplications [Kirchhoff et al, 2001; Shaw-Smith et al, 2004; Le Caignec et al, 2005]. The application of this technology made it possible to identify the genetic basis of CHARGE syndrome, a well recognized multiple malformation disorder [Vissers et al, 2004]

Summary

Introduction

Congenital diaphragmatic hernia (CDH) refers to a group of common developmental defects in the formation of the diaphragm [Tibboel and Gaag, 1996] found in as many as 1/3,000 live births. The most common type of CDH affects the posterolateral region of the diaphragm and is referred to as a Bochdalek hernia. The most common autosomal recessive disorder associated with CDH, Fryns syndrome [OMIM #229850], currently has no identified genetic or biochemical marker [Fryns et al, 1979; Fryns, 1987; Slavotinek, 2004]. This multiple anomaly syndrome is, diagnosed using clinical criteria, resulting in a broad phenotypic array of cases being labeled with Fryns syndrome [Ramsing et al, 2000; Arnold et al, 2003]

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