Mosaic uniparental disomy results in GM1 gangliosidosis with normal enzyme assay

Abstract

Inherited metabolic disorders are traditionally diagnosed using broad and expensive panels of screening tests, often including invasive skin and muscle biopsy. Proponents of next‐generation genetic sequencing have argued that replacing these screening panels with whole exome sequencing (WES) would save money. Here, we present a complex patient in whom WES allowed diagnosis of GM1 gangliosidosis, caused by homozygous GLB1 mutations, resulting in β‐galactosidase deficiency. A 10‐year‐old girl had progressive neurologic deterioration, macular cherry‐red spot, and cornea verticillata. She had marked clinical improvement with initiation of the ketogenic diet. Comparative genomic hybridization microarray showed mosaic chromosome 3 paternal uniparental disomy (UPD). GM1 gangliosidosis was suspected, however β‐galactosidase assay was normal. Trio WES identified a paternally‐inherited pathogenic splice‐site GLB1 mutation (c.75+2dupT). The girl had GM1 gangliosidosis; however, enzymatic testing in blood was normal, presumably compensated for by non‐UPD cells. Severe neurologic dysfunction occurred due to disruptive effects of UPD brain cells.

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

“…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. Among these three cases, the phenotypes involved Pierson syndrome ( LAMB2 ) [ 15 ] and GM1 gangliosidosis ( GLB1 and SLC25A38 ) [ 16 , 17 ]. Currently, only one case of paternal UPD of the entire chromosome 3 has been described with no apparent disease phenotype [ 18 ].…”

Prenatal Diagnosis of Complete Paternal Uniparental Isodisomy for Chromosome 3: A Case Report

“…The proband died from sepsis at 17 months [6] . Another was a 10-year-old girl with epilepsy, severe intellectual disability and progressive neurological decline caused by a homozygous pathogenic splice-site mutation in the GLB1 gene resulting mosaic pat UPD(3) [7] . In addition, microcytic anemia in a infant with sideroblastic anemia type 2 caused by rare nonsense homozygous variant of SLC25A38 gene resulting pat UPD(3) [8] .…”

Runs of Homozygosity and Epigenetic Deregulation of Genomic Imprinting

“…Since ROH can affect a proportion of imprinted genes leading, thereby leading to milder phenotypes of the aforementioned imprinting disorders, it is important to mention somatic ROH leading to acquired UPD (i.e. "somatic epigenomic changes"), which produce neuropsychiatric phenotypes and milder forms of imprinting disorders [10][11][12][13][14]. Such epigenetic changes lead to almost exactly the same phenotypic effect as that observed in cases of somatic genomic variations or somatic mosaicism (i.e.…”