A homozygous mutation in a consanguineous family consolidates the role of ALDH1A3 in autosomal recessive microphthalmia

Abstract

Anomalies of eye development can lead to the rare eye malformations microphthalmia and anophthalmia (small or absent ocular globes), which are genetically very heterogeneous. Several genes have been associated with microphthalmia and anophthalmia, and exome sequencing has contributed to the identification of new genes. Very recently, homozygous variations within ALDH1A3 have been associated with autosomal recessive microphthalmia with or without cysts or coloboma, and with variable subphenotypes of developmental delay/autism spectrum disorder in eight families. In a consanguineous family where three of the five siblings were affected with microphthalmia/coloboma, we identified a novel homozygous missense mutation in ALDH1A3 using exome sequencing. Of the three affected siblings, one had intellectual disability and one had intellectual disability and autism, while the last one presented with normal development. This study contributes further to the description of the clinical spectrum associated with ALDH1A3 mutations, and illustrates the interfamilial clinical variation observed in individuals with ALDH1A3 mutations.

Novel splice-site and missense mutations in theALDH1A3gene underlying autosomal recessive anophthalmia/microphthalmia

“…The presented patients did not have any severe extraocular systemic findings, except for nevus flammeus on the face in individual VII-5 and a variant of Dandy–Walker malformation in individual VII-4; however, we also observed autistic-like behaviours in family CNS_1 individuals VII-4, VII-5, and in family CNS_2 individual IV-6. Recently two other studies also reported intellectual disability and/or autism in anophthalmia/microphthalmia cases with ALDH1A3 mutations 6 8. However, these phenotypes show intrafamilial and interfamilial variation.…”

Novel mutations in ALDH1A3 associated with autosomal recessive anophthalmia/microphthalmia, and review of the literature

“…The ALDH1A3 variant alleles identified in the NAD-binding domain, important for tetramer stabilization include Val71Met, Arg89Cys, Arg96His, Ala145Val, Cys174Tyr, Gly237Arg and Gly282Ala [6, 14–16, 19–21]. In the present study, a further novel variant (p.Glu58Glyfs*5) was identified in the NAD-binding domain.…”

“…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.…”

“…Recently, Liu and coworkers identified compound heterozygous variants in ALDH1A3 in a proband from a non-consanguineous family with anophthalmia [21]. Among the reported ALDH1A3 -associated anophthalmia and microphthalmia cases, 30 have been demonstrated in families of Arab origin including families from Egypt [17], Saudi Arabia [14], Lebanan [16], Morocco [6], Israel [15], and the United Arab Emirates [20], 10 in families of Turkish origin [18], and 12 cases have been found in South and East Asian families including families from Pakistan [3, 6], Iran [19], India [3], Sri Lanka [17] and China [21]. Reported consanguinity rates are high (22–55%) in these populations, which has been associated with an increased risk of autosomal recessive diseases due to homozygosity of regional founder mutations [22].…”

“…ALDH1A3 -associated anophthalmia and microphthalmia, is frequently reported in association with other ocular and extra ocular anomalies, such as the presence of short eyelids, blepharophimosis and reduced palpebral fissures [5, 13, 17, 21], entropion [5], conjunctival symblepharon [17], conjunctival discoloration [17], large eyebrows and synophrys [17, 18], coloboma [5, 14, 16, 17, 20], hypoplasia of the optic tracts and chiasm [5, 6, 15, 17, 18], hypoplastic extra ocular muscles [15, 18], high arched palate [17], refractive errors including both myopia and hyperopia [14, 16], and esotropia [14]. There is a high variability observed in the phenotypic expression of dysmorphic or extra ocular features associated with anophthalmia and microphthalmia, even in individuals with the same ALDH1A3 genetic variants [13, 18, 19].…”