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

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.Peer reviewe

Association of rare MSH6 variants with familial breast cancer

Germline mutations in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2 predispose to Lynch syndrome (also known as hereditary non-polyposis colorectal cancer). Recently, we have shown that the CHEK2 1100delC mutation also is associated with Lynch syndrome/Lynch syndrome-associated families albeit in a polygenic setting. Two of the ten CHEK2 1100delC positive Lynch syndrome families additionally carried a pathogenic MLH1 or MSH6 mutation, suggesting that mutations in mismatch repair genes may be involved in CHEK2 1100delC-associated cancer phenotypes. A phenotype of importance is hereditary breast and colorectal cancer (HBCC), with the CHEK2 1100delC mutation present in almost one-fifth of the families-again in a polygenic setting. In order to evaluate the involvement of MSH6 in polygenic CHEK2 cancer susceptibility, we, here, have analyzed the entire MSH6 coding sequence for genetic alterations in 68 HBCC breast cancer families. Rare MSH6 variants, with population frequencies below 1%, were identified in 11.8% of HBCC breast cancer families, whereas the same variants were identified in only 1.5% of population controls, suggesting that rare MSH6 variants are associated with HBCC breast cancer (P <or = 0.00001). However, screening of the entire MSH6 coding sequence in 68 non-HBCC breast cancer families showed a similar association (8.8 vs. approximately 1.4% in controls, P <or = 0.001), suggesting that rare MSH6 variants are not confined to HBCC breast cancer. Together, our data suggest that rare MSH6 variants may predispose to familial breast cancer. However, none of the rare MSH6 variants are obviously pathogenic, suggesting that a more subtle disease mechanism may operate in breast carcinogenesi

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

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