Maternal Uniparental Isodisomy Causing Autosomal Recessive GM1 Gangliosidosis: A Clinical Report
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CASE PRESENTATION
Maternal Uniparental Isodisomy Causing Autosomal Recessive GM1 Gangliosidosis: A Clinical Report Jessica E. King & Amy Dexter & Inder Gadi & Val Zvereff & Meaghan Martin & Miriam Bloom & Adeline Vanderver & Amy Pizzino & Johanna L. Schmidt
Received: 13 October 2013 / Accepted: 25 March 2014 # National Society of Genetic Counselors, Inc. 2014
Abstract Uniparental disomy is a genetic cause of disease that may result in the inheritance of an autosomal recessive condition. A child with developmental delay and hypotonia was seen and found to have severely abnormal myelination. Lysosomal enzyme testing identified an isolated deficiency of beta-galactosidase. Subsequently, homozygous missense mutations in the galactosidase, beta 1 (GLB1) gene on chromosome 3 were found. Parental testing confirmed inheritance of two copies of the same mutated maternal GLB1 gene, and no paternal copy. SNP analysis was also done to confirm paternity. The patient was ultimately diagnosed with autosomal recessive GM1 gangliosidosis caused by maternal uniparental isodisomy. We provide a review of this patient and others in which uniparental disomy (UPD) of a non-imprinted chromosome unexpectedly caused an autosomal recessive condition. This is the first case of GM1 gangliosidosis reported in the literature to have been caused by UPD. It is important for genetic counselors and other health care providers to be aware of the possibility of autosomal recessive disease caused by UPD. UPD as a cause of autosomal recessive disease drastically changes the recurrence risk for families, and discussions surrounding UPD can be complex. Working with families to understand UPD when it occurs requires a secure and trusting counselor-family relationship. Keywords Autosomal recessive . Uniparental disomy . Isodisomy . GM1 gangliosidosis . GLB1 J. E. King : M. Bloom : A. Vanderver (*) : A. Pizzino : J. L. Schmidt Department of Neurology, Children’s National Medical Center, 111 Michigan Ave. NW, Washington, DC 20010, USA e-mail: [email protected] A. Dexter : I. Gadi : V. Zvereff : M. Martin Laboratory Corporation of America, Research Triangle Park, NC, USA
Introduction Cases of uniparental disomy (UPD) have been reported throughout the literature, both in the context of heterodisomy (i.e. when two inherited homologous chromosomes come from one parent but are not identical) and in the context of isodisomy (i.e. when two inherited homologous chromosomes come from one parent and are identical) (Engel 1995; Engel 2005; Stratchan and Read 2001). Most often the UPD inheritance pattern in human disease occurs in association with defects in imprinting, such as with Angelman syndrome or Prader Willi syndrome (Nussbaum et al. 2007). In these cases, UPD leads to problems with gene expression from the appropriate parent of origin. Chromosomes with known imprinted genes, in which both a maternal and a paternal copy is necessary for proper gene expression, include chromosomes 6, 7, 11, 14, 15, and 20. UPD can be implicated in other human dise
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