Complete Maternal Isodisomy of Chromosome 3 in a Child with Recessive Dystrophic Epidermolysis Bullosa but No Other Phenotypic Abnormalities

Abstract

The mechanobullous disease Hallopeau-Siemens recessive dystrophic epidermolysis bullosa (HS-RDEB) results from mutations in the type VII collagen gene (COL7A1) on chromosome 3p21.31. Typically, there are frameshift, splice site, or nonsense mutations on both alleles. In this report, we describe a patient with HS-RDEB, who was homozygous for a new frameshift mutation, 345insG, in exon 3 of COL7A1. However, sequencing of parental DNA showed that although the patient's mother was a heterozygous carrier of this mutation, the father's DNA contained only wild-type sequence. Microsatellite marker analysis confirmed paternity and genotyping of 28 microsatellites spanning chromosome 3 revealed that the affected child was homozygous for every marker tested with all alleles originating from a single maternal chromosome 3. Thus, the HS-RDEB phenotype in this patient is due to complete maternal isodisomy of chromosome 3 and reduction to homozygosity of the mutant COL7A1 gene locus. To our knowledge, there are no published reports of uniparental disomy (UPD) in HS-RDEB; moreover, this case represents only the third example of UPD of chromosome 3 to be reported. The severity of the HS-RDEB in this case was similar to other affected individuals and no additional phenotypic abnormalities were observed, suggesting an absence of maternally imprinted genes on chromosome 3.

Recessive dystrophic epidermolysis bullosa caused by ade novointerstitial deletion spanningCOL7A1and a hemizygous splicing mutation intrans

“…UPD has been implicated in a number of genodermatoses, including Netherton syndrome, junctional epidermolysis bullosa and RDEB . By contrast, the occurrence of de novo microdeletion in an autosomal recessive disorder is extremely rare, and to the best of our knowledge, this event has only been reported once for RDEB, when Titeux et al .…”

Epidermolysis bullosa. II. Type VII collagen mutations and phenotype-genotype correlations in the dystrophic subtypes

“…Specifically, a recent report described a patient with HS-RDEB who was homozygotic for a novel frameshift mutation, 345insG, in exon 3 of COL7A1. 67 However, sequencing of parental DNA showed that although the patient's mother was a heterozygotic carrier of this mutation, the father's DNA contained only the wild-type sequence. Microsatellite analysis confirmed paternity, and genotyping of the entire chromosome 3 by microsatellite markers showed that the affected child was homozygotic for every marker tested, which originated from a single maternal allele in chromosome 3.…”

The consequences of uniparental disomy and copy number neutral loss-of-heterozygosity during human development and cancer

“…Recently, studies comparing constitutional and tumour DNA genotypes revealed that UPD occurs in a variety of tumour types including neuroblastomas (Carén et al, 2008), clear cell renal carcinomas (Toma et al, 2008), pancreatic adenocarcinomas (Harada et al, 2008) and breast cancer (Murthy et al, 2002; Tuna et al, 2010) with most studies being performed on haematological malignancies (Fitzgibbon et al, 2005; Flotho et al, 2007; Mullighan et al, 2007; Radtke et al, 2009; Walter et al, 2009; Bullinger et al, 2010) (Figure 3). These studies have revealed that UPD can occur in almost any chromosome, but it is becoming evident that UPDs are non‐randomly distributed with cooperation occurring between the acquired UPD and gene mutations.…”

“…Known homozygous mutated tumour suppressor or oncogenes are labelled in black and imprinted genes mapping to common regions of UPD are labelled in red. (Data taken from Lips et al, 2007; Tuna et al, 2010; Midorikawa et al, 2006; Walter et al, 2009; Fitzgibbon et al, 2005; Bullinger et al, 2010.)…”