A genetic and clinical study of individuals with nonsyndromic retinopathy consequent upon sequence variants in HGSNAT, the gene associated with Sanfilippo C mucopolysaccharidosis.
A genetic and clinical study of individuals with nonsyndromic retinopathy consequent upon sequence variants in HGSNAT, the gene associated with Sanfilippo C mucopolysaccharidosis.
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DOI：
10.1002/ajmg.c.31822
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发表时间：
2020-09
期刊：
影响因子：
--
通讯作者：
Webster AR
中科院分区：
文献类型：
--
作者：
Schiff ER;Daich Varela M;Robson AG;Pierpoint K;Ba-Abbad R;Nutan S;Zein WM;Ullah E;Huryn LA;Tuupanen S;Mahroo OA;Michaelides M;Burke D;Harvey K;Arno G;Hufnagel RB;Webster AR
据报道，基因HGSNAT（乙酰肝素-α-氨基葡萄糖苷N-乙酰转移酶）中的致病性变体是两种不同隐性疾病的基础，这取决于特定的基因型，即粘多糖沉积症IIIC型（MPSIIIC）-一种严重的儿童期发病的溶酶体贮积症，以及成人期发病的非综合征性视网膜色素变性（RP）。在这里，我们描述了迄今为止最大的HGSNAT相关非综合征RP患者队列，并描述了他们的视网膜表型，白细胞酶活性和可能的致病基因型。我们在17个个体（15个家族）中鉴定了双等位基因HGSNAT变体作为其RP的可能原因。没有人表现出MPSIIIC的任何其他症状。所有患者的白细胞中HGSNAT酶活性均轻度但显著降低。视网膜疾病通常为迟发性，显示黄斑旁视网膜同心区域的进行性变性，保留但视网膜电图反应降低。症状、电生理学和影像学提示视杆细胞是最初受损的细胞。HGSNAT酶检测有助于解决相容患者的诊断困境。我们发现了七种新的序列变体[p。（Arg239Cys）; p.（Ser296Leu）; p.（Phe428Cys）; p.（Gly248Ala）; p. 1543 - 2A>C; c.1708delA]，其中三个被认为是视网膜疾病特异性等位基因。最常见的视网膜疾病特异性等位基因p。（Ala 615 Thr）等位基因分别在7个家系和4个家系中的8个个体和5个个体中存在杂合和纯合。一个家庭中的两个兄弟姐妹，虽然HGSNAT基因座相同，但视网膜疾病不一致，表明反式作用遗传或环境修饰因素的影响。
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.
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影响因子：
56.9
作者：
BAME, KJ;ROME, LH
通讯作者：
ROME, LH
影响因子：
3.8
作者：
Ruijter, G. J. G.;Valstar, M. J.;Wijburg, F. A.
通讯作者：
Wijburg, F. A.
影响因子：
4.2
作者：
Valstar, M. J.;Ruijter, G. J. G.;Wijburg, F. A.
通讯作者：
Wijburg, F. A.
DOI：
10.1038/ejhg.2014.283
发表时间：
2015-10
期刊：
European journal of human genetics : EJHG
影响因子：
--
作者：
Lenassi E;Vincent A;Li Z;Saihan Z;Coffey AJ;Steele-Stallard HB;Moore AT;Steel KP;Luxon LM;Héon E;Bitner-Glindzicz M;Webster AR
通讯作者：
Webster AR
影响因子：
4.4
作者：
Georgiou, Michalis;Robson, Anthony G.;Michaelides, Michel
通讯作者：
Michaelides, Michel