Familial Skewed X Chromosome Inactivation in Adrenoleukodystrophy Manifesting Heterozygotes from a Chinese Pedigree

Abstract

BackgroundX-linked adrenoleukodystrophy (X-ALD) is an inherited neurodegenerative disorder caused by mutations in the ABCD1 gene. Approximately 20% of X-ALD female carriers may develop neurological symptoms. Skewed X chromosome inactivation (XCI) has been proposed to influence the manifestation of symptoms in X-ALD carriers, but data remain conflicting so far. We identified a three generation kindred, with five heterozygous females, including two manifesting carriers. XCI pattern and the ABCD1 allele expression were assessed in order to determine if symptoms in X-ALD carriers could be related to skewed XCI and whether skewing within this family is more consistent with genetically influenced or completely random XCI.ResultsWe found a high frequency of skewing in this family. Four of five females had skewed XCI, including two manifesting carriers favoring the mutant allele, one asymptomatic carrier favoring the normal allele, and one female who was not an X-ALD carrier. Known causes of skewing, such as chromosomal abnormalities, selection against deleterious alleles, XIST promoter mutations, were not consistent with our results.ConclusionsOur data support that skewed XCI in favor of the mutant ABCD1 allele would be associated with the manifestation of heterozygous symptoms. Furthermore, XCI skewing in this family is genetically influenced. However, the underlying mechanism remains to be substantiated by further experiments.

De novo mutations ofKIAA2022in females cause intellectual disability and intractable epilepsy

“…A reduced penetrance and variable expression in females and a more severe phenotype in males versus females is a common observation in many X-linked disorders, and may be explained by XCI patterns in females 18–22. Our female patient 6 and the patient previously reported by Moyses-Oliveira et al 9 support this theory.…”

Identification of a novel PHEX mutation in a Chinese family with X-linked hypophosphatemic rickets using exome sequencing

“…The PHEX gene is subject to random X chromosome inactivation (XCI) and some escape from inactivation has been reported (Holm et al, 2001;Song et al, 2007), and the Brought to you by | Karolinska Institute Authenticated Download Date | 6/2/15 2:28 AM degree of XCI may contribute to the phenotypic variability. Skewed XCI that prevents the expression of the wild-type alleles may explain phenotypic similarity between heterozygous females and hemizygous males (Haack et al, 2012;Wang et al, 2013).…”

Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease

“…When a disease gene is X-linked, skewed X-inactivation can cause variable penetrance of pathogenic mutations in female carriers (Van den Veyver 2001). Examples of this phenomenon involve mutations in the TIMM8A gene (Xq22.1) in dystonia-deafness syndrome (Plenge et al 1999), the EBP gene (Xp11.23) in X-linked dominant chondrodysplasia punctata (Shirahama et al 2003), the FLNA gene (Xq28) in otopalatodigital type 1 syndrome (Hidalgo-Bravo et al 2005), the ABCD1 gene (Xq28) in a family with X-linked adrenoleukodystrophy (Wang et al 2013b) and the ZIC3 gene (Xq26.3) in a family with complex heart defects (Chhin et al 2007). It should, however, be pointed out that some ZIC3 mutations are characterized by reduced penetrance in males, a finding that cannot be explained by skewed X-inactivation (Mégarbané et al 2000).…”