Schiff, ER;
Varela, MD;
Robson, AG;
Pierpoint, K;
Ba-Abbad, R;
Nutan, S;
Zein, WM;
... Webster, AR; + view all
(2020)
A genetic and clinical study of individuals with nonsyndromic retinopathy consequent upon sequence variants in HGSNAT, the gene associated with Sanfilippo C mucopolysaccharidosis.
American Journal of Medical Genetics Part C: Seminars in Medical Genetics
10.1002/ajmg.c.31822.
(In press).
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Abstract
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.
| Type: | Article |
|---|---|
| Title: | A genetic and clinical study of individuals with nonsyndromic retinopathy consequent upon sequence variants in HGSNAT, the gene associated with Sanfilippo C mucopolysaccharidosis |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/ajmg.c.31822 |
| Publisher version: | http://dx.doi.org/10.1002/ajmg.c.31822 |
| Language: | English |
| Additional information: | This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2020 The Authors |
| Keywords: | HGSNAT, inherited retinal disease, retinopathy |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10107966 |
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