TY - JOUR
T1 - Novel variants in PNPLA6 causing syndromic retinal dystrophy
AU - Wu, Shijing
AU - Sun, Zixi
AU - Zhu, Tian
AU - Weleber, Richard G.
AU - Yang, Paul
AU - Wei, Xing
AU - Pennesi, Mark E.
AU - Sui, Ruifang
N1 - Funding Information:
The authors thank the patients who participated in the study. This work was supported by the National Natural Science Foundation of China ( 81873687 ), Chinese Academy of Medical Sciences ( CAMS ) Innovation Fund for Medical Sciences (CIFMS 2016–12M-1–002), unrestricted grant from Research to Prevent Blindness (Casey Eye Institute), P30 Core Grant NIH P30EY010572 (Casey Eye Institute).
Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2021/1
Y1 - 2021/1
N2 - PNPLA6-related disorders include several phenotypes, such as Boucher–Neuhäuser syndrome, Gordon Holmes syndrome, spastic paraplegia, photoreceptor degeneration, Oliver-McFarlane syndrome and Laurence-Moon syndrome. In this study, detailed clinical evaluations and genetic testing were performed in five (4 Chinese and 1 Caucasian/Chinese) syndromic retinal dystrophy patients. Genotype-phenotype correlations were analyzed based on review of the literatures of previously published PNPLA6-related cases. The mean age of patients and at first visit were 20.8 years (11, 12, 25, 28, 28) and 14.2 years (4, 7, 11, 24, 25), respectively. They all presented with severe chorioretinal dystrophy and profoundly decreased vision. The best corrected visual acuity (BCVA) ranged from 20/200 to 20/2000. Systemic manifestations included cerebellar ataxia, hypogonadotropic hypogonadism and hair anomalies. Six novel and three reported pathogenic variants in PNPLA6 (NM_001166111) were identified. The genotypes of the five cases are: c.3134C > T (p.Ser1045Leu) and c.3846+1G > A, c.3547C > T (p.Arg1183Trp) and c.1841+3A > G, c.3436G > A (p.Ala1146Thr) and c.2212-10A > G, c.3436G > A (p.Ala1146Thr) and c.2266C > T (p.Gln756*), c.1238_1239insC (p.Leu414Serfs*28) and c.3130A > G (p.Thr1044Ala). RT-PCR confirmed that the splicing variants indeed led to abnormal splicing. Missense variants p.Thr1044Ala, p.Ser1045Leu, p.Ala1146Thr, p.Arg1183Trp and c.3846+1G > A are located in Patatin-like phospholipase (Pat) domain. In conclusion, we report the phenotypes in five patients with PNPLA6 associated syndromic retinal dystrophy with variable systemic involvement and typical choroideremia-like fundus changes. Ocular manifestations may be the first and the only findings for years. All of our patients carried one severe deleterious variant (stop-gain or splicing variant) and one milder variant (missense variant). Retinal involvement was significantly correlated with severe deleterious variants and variants in Pat domain.
AB - PNPLA6-related disorders include several phenotypes, such as Boucher–Neuhäuser syndrome, Gordon Holmes syndrome, spastic paraplegia, photoreceptor degeneration, Oliver-McFarlane syndrome and Laurence-Moon syndrome. In this study, detailed clinical evaluations and genetic testing were performed in five (4 Chinese and 1 Caucasian/Chinese) syndromic retinal dystrophy patients. Genotype-phenotype correlations were analyzed based on review of the literatures of previously published PNPLA6-related cases. The mean age of patients and at first visit were 20.8 years (11, 12, 25, 28, 28) and 14.2 years (4, 7, 11, 24, 25), respectively. They all presented with severe chorioretinal dystrophy and profoundly decreased vision. The best corrected visual acuity (BCVA) ranged from 20/200 to 20/2000. Systemic manifestations included cerebellar ataxia, hypogonadotropic hypogonadism and hair anomalies. Six novel and three reported pathogenic variants in PNPLA6 (NM_001166111) were identified. The genotypes of the five cases are: c.3134C > T (p.Ser1045Leu) and c.3846+1G > A, c.3547C > T (p.Arg1183Trp) and c.1841+3A > G, c.3436G > A (p.Ala1146Thr) and c.2212-10A > G, c.3436G > A (p.Ala1146Thr) and c.2266C > T (p.Gln756*), c.1238_1239insC (p.Leu414Serfs*28) and c.3130A > G (p.Thr1044Ala). RT-PCR confirmed that the splicing variants indeed led to abnormal splicing. Missense variants p.Thr1044Ala, p.Ser1045Leu, p.Ala1146Thr, p.Arg1183Trp and c.3846+1G > A are located in Patatin-like phospholipase (Pat) domain. In conclusion, we report the phenotypes in five patients with PNPLA6 associated syndromic retinal dystrophy with variable systemic involvement and typical choroideremia-like fundus changes. Ocular manifestations may be the first and the only findings for years. All of our patients carried one severe deleterious variant (stop-gain or splicing variant) and one milder variant (missense variant). Retinal involvement was significantly correlated with severe deleterious variants and variants in Pat domain.
KW - Boucher-Neuhäuser syndrome
KW - Choroideremia-like
KW - Oliver-McFarlane syndrome
KW - PNPLA6 gene
KW - Syndromic retinal dystrophy
UR - http://www.scopus.com/inward/record.url?scp=85094569874&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85094569874&partnerID=8YFLogxK
U2 - 10.1016/j.exer.2020.108327
DO - 10.1016/j.exer.2020.108327
M3 - Article
C2 - 33141049
AN - SCOPUS:85094569874
SN - 0014-4835
VL - 202
JO - Experimental Eye Research
JF - Experimental Eye Research
M1 - 108327
ER -