Exome sequencing for mucolipidosis III: Detection of a novel GNPTAB gene mutation in a patient with a very mild phenotype

Abstract

Mucolipidosis II and III alpha/beta (ML II/III alpha/beta) are rare autosomal recessive lysosomal storage diseases that are caused by a deficiency of UDP-GlcNAc:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase, the enzyme responsible for the synthesis of the mannose 6-phosphate targeting signal on lysosomal hydrolases. A Brazilian patient suspected of having a very mild ML III was investigated using whole next-generation sequencing (NGS). Two mutations in the GNPTAB gene were detected and confirmed to be in trans status by parental analysis: c.1208T>C (p.Ile403Thr), previously reported as being pathogenic, and the novel mutation c.1723G>A (p.Gly575Arg). This study demonstrates the effectiveness of using whole NGS for the molecular diagnosis of very mild ML III alpha/beta patients.

Clinical Characterization of Mucolipidoses II and III: A Multicenter Study

“…possible using whole genome sequencing. 21 The overall inbreeding rate in our sample was higher than that observed in the literature (8 vs. 1.5-0%). The incidence may vary when inbreeding occurs, as in Ireland, where the prevalence of ML is 1.56:100,000 live births and in "Irish Travelers," a population with a high rate of inbreeding is 114:100,000.…”

“…All subjects attended regular school and did not demonstrate apparent cognitive deficit. No deaths were reported, with the age of the patients being evaluated (21,43, and 46 years).…”

The lysosomal storage disorders mucolipidosis type II, type III alpha/beta, and type III gamma: Update onGNPTABandGNPTGmutations

“…The clinical diagnosis of MLII or MLIII can be confirmed by biochemical analysis of patient's material. Defects in GlcNAc‐1‐phosphotransferase result in missorting of lysosomal enzymes (Figure b), which can be easily detected by measurement of lysosomal enzyme activities in plasma, dried blood, and media from cultured fibroblasts or amniocytes (Alegra et al, ; Pohl et al, ; Sperb‐Ludwig et al, ; Steet et al, ; Tiede et al, ; Tiede, Storch, et al, ; Velho et al, ). Thereby, a 5‐ to 20‐fold increase in lysosomal enzyme activities is considered to be pathogenic.…”

“…For detection of the GNPTAB and GNPTG variants Sanger sequencing was predominantly applied. However, next‐generation sequencing technologies, for example, whole‐exome sequencing followed by validation of the mutation by Sanger sequencing, was also used for variant identification in a number of studies (Costain et al, ; Hashemi‐Gorji, Ghafouri‐Fard, Salehpour, Yassaee, & Miryounesi, ; Khan, Hussain, Sher, Zubaida, & Naeem, ; Retterer et al, ; Schrader et al, ; Soden et al, ; Sperb‐Ludwig et al, ; Zrhidri et al, ; Fernández‐Marmiesse et al, ; Yang et al, ). All novel GNPTAB and GNPTG mutations were identified by the authors of this study in families from Brazil, Chile, Germany, Italy, Portugal, the Netherlands, Turkey, United Kingdom, and United States.…”

Molecular Characterization of a Novel Splicing Mutation Underlying Mucopolysaccharidosis (MPS) Type VI—Indirect Proof of Principle on Its Pathogenicity

“…This technology allows the sequencing of either the whole genome/exome or that of selected panels of genes, through a process known as targeted sequencing. Targeted sequencing in particular is now implemented in many labs and this technology is actively speeding up the solution of several diagnostic problems in the LSDs field, as demonstrated by several teams [6][7][8][9][10][11][12][13][14][15][16][17][18]. While being well known that with this unparalleled capacity, NGS is speeding up molecular diagnostics, it is also true that whenever a novel variant is detected, its pathogenicity must be carefully assessed.…”