Whole-exome sequencing reveals a novel frameshift mutation in the FAM161A gene causing autosomal recessive retinitis pigmentosa in the Indian population
Abstract:Retinitis pigmentosa (RP) is a heterogenous group of inherited retinal degenerations caused by mutations in at least 50 genes. To identify genetic mutations underlying autosomal recessive RP (arRP), we performed whole-exome sequencing study on two consanguineous marriage Indian families (RP-252 and RP-182) and 100 sporadic RP patients. Here we reported novel mutation in FAM161A in RP-252 and RP-182 with two patients affected with RP in each family. The FAM161A gene was identified as the causative gene for RP28… Show more
“…Mutations in this gene are the most common cause of ARRP in Israel (18.2%, Fig. 1 a) while the frequency elsewhere is relatively low (ranging from 0.003 to 2% 17 , 19 , 21 , 22 , 28 ). Figure 1 Distribution of ARRP causative genes and ethnic origin of FAM161A families in the cohort of Israeli patients.…”
Section: Introductionmentioning
confidence: 99%
“…Since the identification of FAM161A as a cause for ARRP in 2010, 13 pathogenic mutations have been reported ( Supplementary Fig. S1 and Supplementary Table S1) 9,10,[17][18][19][20][21][22][23][24][25][26][27] . Two of these mutations (frameshift c.1355_6del and nonsense c.1567C > T) were originally identified to be relatively common among the Jewish population in Israel 9 and two were reported in Palestinian families 9,20 .…”
mentioning
confidence: 99%
“…Mutations in this gene are the most common cause of ARRP in Israel (18.2%, Fig. 1a) while the frequency elsewhere is relatively low (ranging from 0.003 to 2% 17,19,21,22,28 ).…”
mentioning
confidence: 99%
“…To date, a total of 82 patients with ARRP caused by FAM161A mutations have been reported in various publications (42 residing in Israel and 53 worldwide), with a phenotype that largely falls within the spectrum described in other genes causing ARRP 9,10,[17][18][19][20][21][22]28 . In the current study we further explore the clinical phenotype in a large cohort of 100 Israeli patients harboring FAM161A mutations for whom clinical data was available.…”
FAM161A mutations are the most common cause of autosomal recessive retinitis pigmentosa in the Israeli-Jewish population. We aimed to characterize the spectrum of FAM161A-associated phenotypes and identify characteristic clinical features. We identified 114 bi-allelic FAM161A patients and obtained clinical records of 100 of these patients. The most frequent initial symptom was night blindness. Best-corrected visual acuity was largely preserved through the first three decades of life and severely deteriorated during the 4th–5th decades. Most patients manifest moderate-high myopia. Visual fields were markedly constricted from early ages, but maintained for decades. Bone spicule-like pigmentary changes appeared relatively late, accompanied by nummular pigmentation. Full-field electroretinography responses were usually non-detectable at first testing. Fundus autofluorescence showed a hyper-autofluorescent ring around the fovea in all patients already at young ages. Macular ocular coherence tomography showed relative preservation of the outer nuclear layer and ellipsoid zone in the fovea, and frank cystoid macular changes were very rare. Interestingly, patients with a homozygous nonsense mutation manifest somewhat more severe disease. Our clinical analysis is one of the largest ever reported for RP caused by a single gene allowing identification of characteristic clinical features and may be relevant for future application of novel therapies.
“…Mutations in this gene are the most common cause of ARRP in Israel (18.2%, Fig. 1 a) while the frequency elsewhere is relatively low (ranging from 0.003 to 2% 17 , 19 , 21 , 22 , 28 ). Figure 1 Distribution of ARRP causative genes and ethnic origin of FAM161A families in the cohort of Israeli patients.…”
Section: Introductionmentioning
confidence: 99%
“…Since the identification of FAM161A as a cause for ARRP in 2010, 13 pathogenic mutations have been reported ( Supplementary Fig. S1 and Supplementary Table S1) 9,10,[17][18][19][20][21][22][23][24][25][26][27] . Two of these mutations (frameshift c.1355_6del and nonsense c.1567C > T) were originally identified to be relatively common among the Jewish population in Israel 9 and two were reported in Palestinian families 9,20 .…”
mentioning
confidence: 99%
“…Mutations in this gene are the most common cause of ARRP in Israel (18.2%, Fig. 1a) while the frequency elsewhere is relatively low (ranging from 0.003 to 2% 17,19,21,22,28 ).…”
mentioning
confidence: 99%
“…To date, a total of 82 patients with ARRP caused by FAM161A mutations have been reported in various publications (42 residing in Israel and 53 worldwide), with a phenotype that largely falls within the spectrum described in other genes causing ARRP 9,10,[17][18][19][20][21][22]28 . In the current study we further explore the clinical phenotype in a large cohort of 100 Israeli patients harboring FAM161A mutations for whom clinical data was available.…”
FAM161A mutations are the most common cause of autosomal recessive retinitis pigmentosa in the Israeli-Jewish population. We aimed to characterize the spectrum of FAM161A-associated phenotypes and identify characteristic clinical features. We identified 114 bi-allelic FAM161A patients and obtained clinical records of 100 of these patients. The most frequent initial symptom was night blindness. Best-corrected visual acuity was largely preserved through the first three decades of life and severely deteriorated during the 4th–5th decades. Most patients manifest moderate-high myopia. Visual fields were markedly constricted from early ages, but maintained for decades. Bone spicule-like pigmentary changes appeared relatively late, accompanied by nummular pigmentation. Full-field electroretinography responses were usually non-detectable at first testing. Fundus autofluorescence showed a hyper-autofluorescent ring around the fovea in all patients already at young ages. Macular ocular coherence tomography showed relative preservation of the outer nuclear layer and ellipsoid zone in the fovea, and frank cystoid macular changes were very rare. Interestingly, patients with a homozygous nonsense mutation manifest somewhat more severe disease. Our clinical analysis is one of the largest ever reported for RP caused by a single gene allowing identification of characteristic clinical features and may be relevant for future application of novel therapies.
“…Proband H45 harbors a nonsense mutation (p.Q302X) in FAM161A. Loss-of-function mutations in this gene are reported to cause autosomal recessive retinitis pigmentosa (36,37). Interestingly, HM is coupled with these diseases in patients (38).…”
The etiology of the highly myopic condition has been unclear for decades. We investigated the genetic contributions to early-onset high myopia (EOHM), which is defined as having a refraction of less than or equal to −6 diopters before the age of 6, when children are less likely to be exposed to high educational pressures. Trios (two nonmyopic parents and one child) were examined to uncover pathogenic mutations using whole-exome sequencing. We identified parent-transmitted biallelic mutations or de novo mutations in asyet-unknown or reported genes in 16 probands. Interestingly, an increased rate of de novo mutations was identified in the EOHM patients. Among the newly identified candidate genes, a BSG mutation was identified in one EOHM proband. Expanded screening of 1,040 patients found an additional four mutations in the same gene. Then, we generated Bsg mutant mice to further elucidate the functional impact of this gene and observed typical myopic phenotypes, including an elongated axial length. Using a trio-based exonic screening study in EOHM, we deciphered a prominent role for de novo mutations in EOHM patients without myopic parents. The discovery of a disease gene, BSG, provides insights into myopic development and its etiology, which expands our current understanding of high myopia and might be useful for future treatment and prevention.early-onset high myopia | de novo mutations | BSG | rare inherited mutations
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