A genetic and clinical study of individuals with nonsyndromic retinopathy consequent upon sequence variants in HGSNAT, the gene associated with Sanfilippo C mucopolysaccharidosis
| Autor: | Elena R. Schiff, Omar A. Mahroo, Derek Burke, Gavin Arno, Rola Ba-Abbad, Karen Pierpoint, Ehsan Ullah, Savita Nutan, Malena Daich Varela, Katie Harvey, Laryssa A. Huryn, Anthony G. Robson, Robert B. Hufnagel, Andrew R. Webster, Wadih M. Zein, Michel Michaelides, Sari Tuupanen |
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| Rok vydání: | 2020 |
| Předmět: |
Adult
Male Adolescent Genotype Mucopolysaccharidosis Locus (genetics) Biology Retina Article chemistry.chemical_compound Mucopolysaccharidosis III Young Adult Retinal Diseases Acetyltransferases HGSNAT Retinitis pigmentosa retinopathy Genetics medicine Leukocytes Humans Allele Child Gene Genetics (clinical) Mucopolysaccharidosis Type IIIC Retinal Middle Aged medicine.disease Pedigree chemistry inherited retinal disease Female Retinitis Pigmentosa |
| Zdroj: | American journal of medical genetics. Part C, Seminars in medical genetics |
| ISSN: | 1552-4876 |
| Popis: | Pathogenic variants in the gene HGSNAT (heparan-α-glucosaminide N-acetyltransferase) have been reported to underlie two distinct recessive conditions, depending on the specific genotype, mucopolysaccharidosis type IIIC (MPSIIIC)-a severe childhood-onset lysosomal storage disorder, and adult-onset nonsyndromic retinitis pigmentosa (RP). Here we describe the largest cohort to-date of HGSNAT-associated nonsyndromic RP patients, and describe their retinal phenotype, leukocyte enzymatic activity, and likely pathogenic genotypes. We identified biallelic HGSNAT variants in 17 individuals (15 families) as the likely cause of their RP. None showed any other symptoms of MPSIIIC. All had a mild but significant reduction of HGSNAT enzyme activity in leukocytes. The retinal condition was generally of late-onset, showing progressive degeneration of a concentric area of paramacular retina, with preservation but reduced electroretinogram responses. Symptoms, electrophysiology, and imaging suggest the rod photoreceptor to be the cell initially compromised. HGSNAT enzymatic testing was useful in resolving diagnostic dilemmas in compatible patients. We identified seven novel sequence variants [p.(Arg239Cys); p.(Ser296Leu); p.(Phe428Cys); p.(Gly248Ala); p.(Gly418Arg), c.1543-2A>C; c.1708delA], three of which were considered to be retina-disease-specific alleles. The most prevalent retina-disease-specific allele p.(Ala615Thr) was observed heterozygously or homozygously in 8 and 5 individuals respectively (7 and 4 families). Two siblings in one family, while identical for the HGSNAT locus, but discordant for retinal disease, suggest the influence of trans-acting genetic or environmental modifying factors. |
| Databáze: | OpenAIRE |
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