title: Mitotic Intragenic Recombination: A Mechanism of Survival for Several Congenital Disorders of Glycosylation.
abstract: Congenital disorders of glycosylation (CDGs) are disorders of abnormal protein glycosylation that affect multiple organ systems. Because most CDGs have been described in only a few individuals, our understanding of the associated phenotypes and the mechanisms of individual survival are limited. In the process of studying two siblings, aged 6 and 11 years, with MOGS-CDG and biallelic MOGS (mannosyl-oligosaccharide glucosidase) mutations (GenBank: NM_006302.2; c.[65C>A; 329G>A] p.[Ala22Glu; Arg110His]; c.[370C>T] p.[Gln124(∗)]), we noted that their survival was much longer than the previous report of MOGS-CDG, in a child who died at 74 days of age. Upon mutation analysis, we detected multiple MOGS genotypes including wild-type alleles in their cultured fibroblast and peripheral blood DNA. Further analysis of DNA from cultured fibroblasts of six individuals with compound heterozygous mutations of PMM2 (PMM2-CDG), MPI (MPI-CDG), ALG3 (ALG3-CDG), ALG12 (ALG12-CDG), DPAGT1 (DPAGT1-CDG), and ALG1 (ALG1-CDG) also identified multiple genotypes including wild-type alleles for each. Droplet digital PCR showed a ratio of nearly 1:1 wild-type to mutant alleles for most, but not all, mutations. This suggests that mitotic recombination contributes to the survival and the variable expressivity of individuals with compound heterozygous CDGs. This also provides an explanation for prior observations of a reduced frequency of homozygous mutations and might contribute to increased levels of residual enzyme activity in cultured fibroblasts of individuals with MPI- and PMM2-CDGs.
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA; National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA. Electronic address: megan.kane@nih.gov.
authors.forename: Megan S
authors.initials: MS
authors.lastname: Kane
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA; National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Mariska
authors.initials: M
authors.lastname: Davids
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA; National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Adams
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA.
authors.forename: Lynne A
authors.initials: LA
authors.lastname: Wolfe
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA; National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Helen W
authors.initials: HW
authors.lastname: Cheung
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA; Department of Neurology, Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Gropman
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA; National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Bobby G
authors.initials: BG
authors.lastname: Ng
authors.affiliation: Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
authors.forename: Hudson H
authors.initials: HH
authors.lastname: Freeze
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA; National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Adams
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD 20892, USA; National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA. Electronic address: gahlw@helix.nih.gov.
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
authors.forename: Cornelius F
authors.initials: CF
authors.lastname: Boerkoel
mesh_terms: D000595:Amino Acid Sequence; D002648:Child; D018981:Congenital Disorders of Glycosylation / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005787:Gene Frequency; D015894:Genome, Human; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008938:Mitosis; D008969:Molecular Sequence Data; D009154:Mutation; D011995:Recombination, Genetic; D017422:Sequence Analysis, DNA; D035781:Siblings; D000520:alpha-Glucosidases / Q000235:genetics / Q000378:metabolism
chemical_list: C042059:glucosidase I; D000520:alpha-Glucosidases