Segmental and total uniparental isodisomy (UPiD) as a disease mechanism in autosomal recessive lysosomal disorders: evidence from SNP arrays

Ineke Labrijn-Marks,Hannerieke J M Van Den Hout,Sirpa Ala‐Mello ,Marian A Kroos,Helen Michelakakis,Olga Amaral,Lies H Hoefsloot,Marianne Hoogeveen‐Westerveld ,Marloes Benjamins,Trijnie Dijkhuizen,Frans W Verheijen,Galhana M Somers-Bolman,Ans T Van Der Ploeg,Irene Mavridou,K Naess ,Clara Sá Miranda ,Jasper J Saris,Stijn L.m In ‘T Groen ,W.w.m Pim Pijnappel ,Dicky Halley

doi:10.1038/s41431-019-0348-y

Abstract

Analyses in our diagnostic DNA laboratory include genes involved in autosomal recessive (AR) lysosomal storage disorders such as glycogenosis type II (Pompe disease) and mucopolysaccharidosis type I (MPSI, Hurler disease). We encountered 4 cases with apparent homozygosity for a disease-causing sequence variant that could be traced to one parent only. In addition, in a young child with cardiomyopathy, in the absence of other symptoms, a diagnosis of Pompe disease was considered. Remarkably, he presented with different enzymatic and genotypic features between leukocytes and skin fibroblasts. All cases were examined with microsatellite markers and SNP genotyping arrays. We identified one case of total uniparental disomy (UPD) of chromosome 17 leading to Pompe disease and three cases of segmental uniparental isodisomy (UPiD) causing Hurler-(4p) or Pompe disease (17q). One Pompe patient with unusual combinations of features was shown to have a mosaic segmental UPiD of chromosome 17q. The chromosome 17 UPD cases amount to 11% of our diagnostic cohort of homozygous Pompe patients (plus one case of pseudoheterozygosity) where segregation analysis was possible. We conclude that inclusion of parental DNA is mandatory for reliable DNA diagnostics. Mild or unusual phenotypes of AR diseases should alert physicians to the possibility of mosaic segmental UPiD. SNP genotyping arrays are used in diagnostic workup of patients with developmental delay. Our results show that even small Regions of Homozygosity that include telomeric areas are worth reporting, regardless of the imprinting status of the chromosome, as they might indicate segmental UPiD.

Highlights

Up to date diagnostics of metabolic disorders includes mutation analysis of the causative gene
Using microsatellite markers and SNP microarrays we identified 5 cases of uniparental disomy (UPD) in patients with autosomal recessive lysosomal storage diseases, 4 of which were maternal in origin and 1 was paternal
It concerned one case of Hurler disease and four with Pompe disease including one case with an unusual combination of features. Four of these cases were traced when apparent homozygosity for a Hurler- or Pompe disease-causing variant was found in the patients and only the mothers proved to be carriers

Summary

Introduction

Up to date diagnostics of metabolic disorders includes mutation analysis of the causative gene. Enzyme assays have been considered to be the gold standard for diagnosis of the symptomatic patient, genotyping is a. Data sharing statement Technical details including primer sequences available on request. Extended author information available on the last page of the article. Requirement for inclusion in enzyme replacement programs and is a prerequisite for carrier tests in relatives and DNAbased prenatal diagnosis. For confirmation of allelic segregation, we routinely request parental DNA samples. We will refer to those sequence variants known to cause (Hurler or Pompe) disease in a homozygous or compound heterozygous state as “pathogenic”

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Conclusion