Maternal Uniparental Isodisomy Causing Autosomal Recessive GM1 Gangliosidosis: A Clinical Report

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.

Mosaic uniparental disomy results in GM1 gangliosidosis with normal enzyme assay

“…These findings emphasize the potential of WES to aid in diagnosis of inherited disorders of metabolism (Pierson et al, ). GM1 gangliosidosis has been previously reported in a case of non‐mosaic UPD (King et al, ); however, β‐galactosidase activity was markedly decreased in that case, allowing for easy confirmation of the diagnosis. Our patient illustrates that WES can identify inherited disorders of metabolism, even when functional metabolic testing is normal.…”

POLG mutations presenting as Charcot‐Marie‐Tooth disease

“…In the absence of parental genotype information in typical clinical testing scenarios, any long stretches of homozygosity should be followed up with additional tests as UPD has potentially consequences for genetic counseling of patients. UPD is a rare cause of recessive disease . For example, out of 96 families with unresolved causes of motoneuron disease or ataxia, one person (with spastic paraplegia) was found to have a homozygous mutation in FA2H resulting from UPD .…”

“…UPD is a rare cause of recessive disease. 20 For example, out of 96 families with unresolved causes of motoneuron disease or ataxia, one person (with spastic paraplegia) was found to have a homozygous mutation in FA2H resulting from UPD. 5 However, a recent screening of 214 915 trios revealed a UPD prevalence of 1 in 2000 births in the general population; this is twice the current clinical estimate.…”

Prenatal diagnosis of complete paternal uniparental isodisomy for chromosome 3: a case report

“…Among the 10 cases of maternal UPD(3) with an abnormal phenotype, 6 had clear clinical phenotypes associated with chromosomal recessive disorders, 2 had abnormal chromosome karyotype, 1 had mosaic UPD, and detailed information was not available for 1 case. Among these six cases, the phenotypes included epidermolysis bullosa ( COL7A1 ) [ 9 , 10 ], Fanconi Bickel syndrome ( GLUT2 ) [ 11 ], a congenital disorder of glycosylation type Id ( ALG3 ) [ 12 ], GM1 gangliosidosis ( GLB1 ) [ 13 ], and woolly hair/hypotrichosis ( LIPH ) [ 14 ]. Among the five reported cases of paternal UPD(3), three had a definite phenotype caused by single-gene disorders, one had no apparent disease phenotype, and one presented an abnormal karyotype.…”