“…Arg89CysPakistani2AMFares-Taie et al [6]c.287G > Ap.Arg96HisChinese1ALiu et al [21]c.434C > Tp. Ala145ValSaudi Arabian2MAldahmesh et al [14]c.521G > Ap.Cys174TyrLebanese3AMRoos et al [16]c.709G > Ap.Gly237ArgChinese & Iranian3ALiu et al [21]; Dehghani et al [19]c.845G > Cp.Gly282AlaArabic2MAlabdullatif et al [20]c.964G > Ap.Val322MetIndian1AUllah et al [3]c.1064C > Gp.Pro355ArgEgyptian1AAbouzeid et al [17]. c.1105A > Tp.…”
Section: Resultsmentioning
confidence: 99%
“…1240G > Cp.Gly414ArgPakistani4APresent studyNonsensec.568A > Tp.Lys190Egyptian2AMYahyavi et al [5]c.898G > Tp.Glu300Spanish1MAbouzeid et al [17]c.1165A > Tp.Lys389Hispanic1AMYahyavi et al [5]Splicingc.204 + 1G > AAlteration of the WT donor siteaffecting splicingEgyptian2AMAbouzeid et al [17]c.475 + 1G > TSkipping of exon 5p. Asp159-Pro179 delMoroccan1AMFares-Taie et al [6]c.666G > ASkipping of exon 6p.Trp180_Glu222delTurkish7AMSemerci et al [18]Plaisancié et al [13]c.1391 + 1G > TAlteration of the WT donor siteaffecting splicingEgyptian1AAbouzeid et al [17]Frameshiftc.1310_1311delATp.Tyr437Trpfs*44Pakistani4AUllah et al [3]c.172dupp. Glu58Glyfs*5Pakistani3APresent study
WT wild type, AM anophthalmia and microphthalmia, A anophthalmia, M microphthalmia
Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Since then, mutations of ALDH1A3 have been identified as a cause of autosomal recessive anophthalmia and microphthalmia in 54 individuals to date. Among these families, 50 individuals are from consanguineous families [3, 5, 6, 13–19], one from a non-consanguineous family, [5] and three are sporadic or individual cases [5, 20]. Recently, Liu and coworkers identified compound heterozygous variants in ALDH1A3 in a proband from a non-consanguineous family with anophthalmia [21].…”
Section: Discussionmentioning
confidence: 99%
“…Both syndromic and non-syndromic forms of anophthalmia and microphthalmia have been associated with autosomal recessive, autosomal dominant and X-linked patterns of inheritance, and display extensive genetic heterogeneity [2]. Mutations in numerous genes including RAX , PAX6 , SOX2 , OTX2 , VSX2 , RARB , BMP7 , BCOR , BMP4 , FOXE3 , STRA6 , SMOC1 , SHH , SNX3 , MFRP , PRSS56 , GDF3 , GDF6 , TENM3 , C12orf57 , YAP1, ABCB6 , ATOH7 , VAX1 , NDP , ALDH1A3 and SMARCA4 have all been described in association with microphthalmia, and some, including RAX , PAX6 , SOX2 , OTX2 , RARB , BMP7 , BCOR , BMP4 , FOXE3 , STRA6 , SMOC1 , GDF6 and ALDH1A3 have also been described in association with anophthalmia [3–5]. SOX2 mutations are the major single-gene cause of anophthalmia and microphthalmia, accounting for ~ 10–15% of all cases [6].…”
Section: Introductionmentioning
confidence: 99%
“…Notably, mutations of this gene appear to be the major cause of these conditions in consanguineous families of Pakistani origin [3, 6]. The ALDH1A3 gene encodes a NAD-dependent aldehyde dehydrogenase, which is among one of three retinaldehyde dehydrogenases (the others being ALDH1A1 and ALDH1A2 ) that play a key role in the biosynthesis of retinoic acid from retinaldehyde.…”
BackgroundAutosomal recessive anophthalmia and microphthalmia are rare developmental eye defects occurring during early fetal development. Syndromic and non-syndromic forms of anophthalmia and microphthalmia demonstrate extensive genetic and allelic heterogeneity. To date, disease mutations have been identified in 29 causative genes associated with anophthalmia and microphthalmia, with autosomal dominant, autosomal recessive and X-linked inheritance patterns described. Biallelic ALDH1A3 gene variants are the leading genetic causes of autosomal recessive anophthalmia and microphthalmia in countries with frequent parental consanguinity.MethodsThis study describes genetic investigations in two consanguineous Pakistani families with a total of seven affected individuals with bilateral non-syndromic clinical anophthalmia.ResultsUsing whole exome and Sanger sequencing, we identified two novel homozygous ALDH1A3 sequence variants as likely responsible for the condition in each family; missense mutation [NM_000693.3:c.1240G > C, p.Gly414Arg; Chr15:101447332G > C (GRCh37)] in exon 11 (family 1), and, a frameshift mutation [NM_000693.3:c.172dup, p.Glu58Glyfs*5; Chr15:101425544dup (GRCh37)] in exon 2 predicted to result in protein truncation (family 2).ConclusionsThis study expands the molecular spectrum of pathogenic ALDH1A3 variants associated with anophthalmia and microphthalmia, and provides further insight of the key role of the ALDH1A3 in human eye development.Electronic supplementary materialThe online version of this article (10.1186/s12881-018-0678-6) contains supplementary material, which is available to authorized users.
“…Arg89CysPakistani2AMFares-Taie et al [6]c.287G > Ap.Arg96HisChinese1ALiu et al [21]c.434C > Tp. Ala145ValSaudi Arabian2MAldahmesh et al [14]c.521G > Ap.Cys174TyrLebanese3AMRoos et al [16]c.709G > Ap.Gly237ArgChinese & Iranian3ALiu et al [21]; Dehghani et al [19]c.845G > Cp.Gly282AlaArabic2MAlabdullatif et al [20]c.964G > Ap.Val322MetIndian1AUllah et al [3]c.1064C > Gp.Pro355ArgEgyptian1AAbouzeid et al [17]. c.1105A > Tp.…”
Section: Resultsmentioning
confidence: 99%
“…1240G > Cp.Gly414ArgPakistani4APresent studyNonsensec.568A > Tp.Lys190Egyptian2AMYahyavi et al [5]c.898G > Tp.Glu300Spanish1MAbouzeid et al [17]c.1165A > Tp.Lys389Hispanic1AMYahyavi et al [5]Splicingc.204 + 1G > AAlteration of the WT donor siteaffecting splicingEgyptian2AMAbouzeid et al [17]c.475 + 1G > TSkipping of exon 5p. Asp159-Pro179 delMoroccan1AMFares-Taie et al [6]c.666G > ASkipping of exon 6p.Trp180_Glu222delTurkish7AMSemerci et al [18]Plaisancié et al [13]c.1391 + 1G > TAlteration of the WT donor siteaffecting splicingEgyptian1AAbouzeid et al [17]Frameshiftc.1310_1311delATp.Tyr437Trpfs*44Pakistani4AUllah et al [3]c.172dupp. Glu58Glyfs*5Pakistani3APresent study
WT wild type, AM anophthalmia and microphthalmia, A anophthalmia, M microphthalmia
Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Since then, mutations of ALDH1A3 have been identified as a cause of autosomal recessive anophthalmia and microphthalmia in 54 individuals to date. Among these families, 50 individuals are from consanguineous families [3, 5, 6, 13–19], one from a non-consanguineous family, [5] and three are sporadic or individual cases [5, 20]. Recently, Liu and coworkers identified compound heterozygous variants in ALDH1A3 in a proband from a non-consanguineous family with anophthalmia [21].…”
Section: Discussionmentioning
confidence: 99%
“…Both syndromic and non-syndromic forms of anophthalmia and microphthalmia have been associated with autosomal recessive, autosomal dominant and X-linked patterns of inheritance, and display extensive genetic heterogeneity [2]. Mutations in numerous genes including RAX , PAX6 , SOX2 , OTX2 , VSX2 , RARB , BMP7 , BCOR , BMP4 , FOXE3 , STRA6 , SMOC1 , SHH , SNX3 , MFRP , PRSS56 , GDF3 , GDF6 , TENM3 , C12orf57 , YAP1, ABCB6 , ATOH7 , VAX1 , NDP , ALDH1A3 and SMARCA4 have all been described in association with microphthalmia, and some, including RAX , PAX6 , SOX2 , OTX2 , RARB , BMP7 , BCOR , BMP4 , FOXE3 , STRA6 , SMOC1 , GDF6 and ALDH1A3 have also been described in association with anophthalmia [3–5]. SOX2 mutations are the major single-gene cause of anophthalmia and microphthalmia, accounting for ~ 10–15% of all cases [6].…”
Section: Introductionmentioning
confidence: 99%
“…Notably, mutations of this gene appear to be the major cause of these conditions in consanguineous families of Pakistani origin [3, 6]. The ALDH1A3 gene encodes a NAD-dependent aldehyde dehydrogenase, which is among one of three retinaldehyde dehydrogenases (the others being ALDH1A1 and ALDH1A2 ) that play a key role in the biosynthesis of retinoic acid from retinaldehyde.…”
BackgroundAutosomal recessive anophthalmia and microphthalmia are rare developmental eye defects occurring during early fetal development. Syndromic and non-syndromic forms of anophthalmia and microphthalmia demonstrate extensive genetic and allelic heterogeneity. To date, disease mutations have been identified in 29 causative genes associated with anophthalmia and microphthalmia, with autosomal dominant, autosomal recessive and X-linked inheritance patterns described. Biallelic ALDH1A3 gene variants are the leading genetic causes of autosomal recessive anophthalmia and microphthalmia in countries with frequent parental consanguinity.MethodsThis study describes genetic investigations in two consanguineous Pakistani families with a total of seven affected individuals with bilateral non-syndromic clinical anophthalmia.ResultsUsing whole exome and Sanger sequencing, we identified two novel homozygous ALDH1A3 sequence variants as likely responsible for the condition in each family; missense mutation [NM_000693.3:c.1240G > C, p.Gly414Arg; Chr15:101447332G > C (GRCh37)] in exon 11 (family 1), and, a frameshift mutation [NM_000693.3:c.172dup, p.Glu58Glyfs*5; Chr15:101425544dup (GRCh37)] in exon 2 predicted to result in protein truncation (family 2).ConclusionsThis study expands the molecular spectrum of pathogenic ALDH1A3 variants associated with anophthalmia and microphthalmia, and provides further insight of the key role of the ALDH1A3 in human eye development.Electronic supplementary materialThe online version of this article (10.1186/s12881-018-0678-6) contains supplementary material, which is available to authorized users.
Mutations in the transcription factor genes FOXE3, HSF4, MAF, and PITX3 cause congenital lens defects including cataracts that may be accompanied by defects in other components of the eye or in nonocular tissues. We comprehensively describe here all the variants in FOXE3, HSF4, MAF, and PITX3 genes linked to human developmental defects. A total of 52 variants for FOXE3, 18 variants for HSF4, 20 variants for MAF, and 19 variants for PITX3 identified so far in isolated cases or within families are documented. This effort reveals FOXE3, HSF4, MAF, and PITX3 to have 33, 16, 18, and 7 unique causal mutations, respectively. Loss-of-function mutant animals for these genes have served to model the pathobiology of the associated human defects, and we discuss the currently known molecular function of these genes, particularly with emphasis on their role in ocular development. Finally, we make the detailed FOXE3, HSF4, MAF, and PITX3 variant information available in the Leiden Online Variation Database (LOVD) platform at https://www.LOVD.nl/FOXE3, https://www.LOVD.nl/HSF4, https://www.LOVD.nl/MAF, and https://www.LOVD.nl/PITX3. Thus, this article informs on key variants in transcription factor genes linked to cataract, aphakia, corneal opacity, glaucoma, microcornea, microphthalmia, anterior segment mesenchymal dysgenesis, and Ayme-Gripp syndrome, and facilitates their access through Web-based databases.
BackgroundAnophthalmia and microphthalmia are severe developmental ocular disorders that affect the size of the ocular globe and can be unilateral or bilateral. The disease is found in syndromic as well as non‐syndromic forms. It is genetically caused by chromosomal aberrations, copy number variations and single gene mutations, along with non‐genetic factors such as viral infections, deficiency of vitamin A and an exposure to alcohol or drugs during pregnancy. To date, more than 30 genes having different modes of inheritance patterns are identified as causing anophthalmia and microphthalmia.MethodsIn the present study, a clinical and genetic analysis was performed of six patients with anophthalmia and microphthalmia and/or additional phenotypes of intellectual disability, developmental delay and cerebral palsy from a large consanguineous Pakistani family. Whole exome sequencing followed by data analysis for variants prioritization and validation through Sanger sequencing was performed to identify the disease causing variant(s). American College of Medical Genetics and Genomics (ACMG) guidelines were applied to classify clinical interpretation of the prioritized variants.ResultsClinical investigations revealed that the affected individuals are afflicted with anophthalmia. Three of the patients showed additional phenotype of intellectual disability, developmental delays and other neurological symptoms. Whole exome sequencing of the DNA samples of the affected members in the family identified a novel homozygous stop gain mutation (NM_012186: c.106G>T: p.Glu36*) in Forkhead Box E3 (FOXE3) gene shared by all affected individuals. Moreover, patients segregating additional phenotypes of spastic paraplegia, intellectual disability, hearing loss and microcephaly showed an additional homozygous sequence variant (NM_004722: c.953G>A: p.Arg318Gln) in AP4M1. Sanger sequencing validated the correct segregation of the identified variants in the affected family. ACMG guidelines predicted the variants to be pathogenic.ConclusionsWe have investigated first case of syndromic anophthalmia caused by variants in the FOXE3 and AP4M1. The present findings are helpful for understanding pathological role of the mutations of the genes in syndromic forms of anophthalmia. Furthermore, the study signifies searching for the identification of second variant in families with patients exhibiting variable phenotypes. In addition, the findings will help clinical geneticists, genetic counselors and the affected family with respect to prenatal testing, family planning and genetic counseling.
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