Unraveling the genetic cause of a consanguineous family with unilateral coloboma and retinoschisis: expanding the phenotypic variability of RAX mutations

Huang, Xiu‐Feng; Huang, Zhiqin; Lin, Dan; Wang, Qingfeng; Chen, Zhen-Ji; Jin, Zi‐Bing

doi:10.1038/s41598-017-09276-0

Cited by 13 publications

(12 citation statements)

References 27 publications

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“…This presumably allowed for some residual activity for the RAX protein. Their eye phenotype was very severe (bilateral anophthalmia) except for the patient reported by Huang et al (22), a 14-year-old boy, who had a later developmental eye anomaly (coloboma) and was homozygous for a possibly damaging missense mutation (PolyPhen2 score, 0.873). The remaining patients had a severe and early developmental eye malformation.…”

Section: Discussionmentioning

confidence: 97%

Truncating RAX Mutations: Anophthalmia, Hypopituitarism, Diabetes Insipidus, and Cleft Palate in Mice and Men

Brachet

Kozhemyakina

Boros

et al. 2019

The Journal of Clinical Endocrinology &Amp; Metabolism

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ORCiD numbers: 0000-0001-7955-2534 (C. Brachet).Context: The transcription factor RAX is a paired-type homeoprotein that plays a critical role in eye and forebrain development of vertebrate species. RAX knockout mice have anophthalmia, cleft palate, and an abnormal hypothalamus and display perinatal lethality. In humans, homozygous or compound heterozygous RAX mutations have been reported to cause bilateral microphthalmia or anophthalmia without consistent associated features. Congenital hypopituitarism can be associated with various eye or craniofacial anomalies; however, the co-occurrence of congenital hypopituitarism, anophthalmia, cleft palate, and diabetes insipidus has been very rare. Results:We report the case of a child with anophthalmia, congenital hypopituitarism, diabetes insipidus, and bilateral cleft lip and palate who had a homozygous frameshift truncating mutation c.266delC (p.Pro89Argfs*114) in exon 1 of the RAX gene. Rax knockout mice show loss of ventral forebrain structures, pituitary, and basosphenoid bone and palate and a misplaced anterior pituitary gland along the roof of the oral cavity.Conclusions: Our patient's phenotype was more severe than that reported in other patients. Although most of the previously reported patients with RAX mutations showed either a missense or some less severe mutation in at least one of their RAX alleles, our patient was homozygous for truncating mutations that would yield a severe, null protein phenotype. The severity of the genetic defect, the precise match between the knockout mouse and the patient's endocrine phenotypes, and the prominent roles of RAX in eye and pituitary development and diencephalic patterning suggest that the RAX null mutations could fully account for the observed phenotype. (J Clin Endocrinol Metab

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Section: Discussionmentioning

confidence: 97%

Truncating RAX Mutations: Anophthalmia, Hypopituitarism, Diabetes Insipidus, and Cleft Palate in Mice and Men

Brachet

Kozhemyakina

Boros

et al. 2019

The Journal of Clinical Endocrinology &Amp; Metabolism

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“…Biallelic mutations have been identified in 7 families with a bilateral and severe ocular A/M phenotype (Abouzeid et al 2012;Chassaing et al 2014;Lequeux et al 2008;Voronina et al 2004) and in 1 family with isolated unilateral coloboma and retinoschisis (Huang et al 2017). These mutations are of varying nature (missense, nonsense, frameshift and splicing mutations, and a gene deletion), but all act through a "loss-of-function" mechanism.…”

Section: Rax (Retina and Anterior Neural Fold Homeobox)mentioning

confidence: 99%

Genetics of anophthalmia and microphthalmia. Part 1: Non-syndromic anophthalmia/microphthalmia

et al. 2019

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Eye formation is the result of coordinated induction and differentiation processes during embryogenesis. Disruption of any one of these events has the potential to cause ocular growth and structural defects, such as anophthalmia and microphthalmia (A/M). A/M can be isolated or occur with systemic anomalies, when they may form part of a recognizable syndrome. Their etiology includes genetic and environmental factors; several hundred genes involved in ocular development have been identified in humans or animal models. In humans, around 30 genes have been repeatedly implicated in A/M families, although many other genes have been described in single cases or families, and some genetic syndromes include eye anomalies occasionally as part of a wider phenotype. As a result of this broad genetic heterogeneity, with one or two notable exceptions, each gene explains only a small percentage of cases. Given the overlapping phenotypes, these genes can be most efficiently tested on panels or by whole exome/genome sequencing for the purposes of molecular diagnosis. However, despite whole exome/genome testing more than half of patients currently remain without a molecular diagnosis. The proportion of undiagnosed cases is even higher in those individuals with unilateral or milder phenotypes. Furthermore, even when a strong gene candidate is available for a patient, issues of incomplete penetrance and germinal mosaicism make diagnosis and genetic counselling challenging. In this review, we present the main genes implicated in nonsyndromic human A/M phenotypes and, for practical purposes, classify them according to the most frequent or predominant phenotype each is associated with. Our intention is that this will allow clinicians to rank and prioritize their molecular analyses and interpretations according to the phenotypes of their patients.

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“…In humans, mutations in several transcription factor genes have been reported to cause disruption of vertebrate eye development or maintenance. [ 10 11 12 13 14 15 27 28 29 30 31 32 ] This led to the hypothesis that polymorphisms in these genes may also predispose towards the risk of congenital eye disorders. In our previous studies on mutation screening in candidate genes for congenital cataract and microphthalmia, we observed that the frequency of two polymorphisms FOXE3 -p.Ala170Ala and PITX3 -p.Ile95Ile was higher in congenital cataract and microphthalmia cases as compared to controls.…”

Section: Discussionmentioning

confidence: 99%

Association of FOXE3-p.Ala170Ala and PITX3-p.Ile95Ile polymorphisms with congenital cataract and microphthalmia

Vidya¹,

Ganatra

Vasavada

et al. 2018

J Ophthalmic Vis Res

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Purpose:To investigate the association of FOXE3-p.Ala170Ala (rs34082359) and PITX3-p.Ile95Ile (rs2281983) polymorphisms with congenital cataract and microphthalmia in a western Indian population.Methods:FOXE3-p.Ala170Ala (c.510C>T) and PITX3-p.Ile95Ile (c.285C>T) polymorphisms were genotyped in 561 subjects consisting of 242 cases with congenital cataract, 52 with microphthalmia, and 267 controls using polymerase chain reaction-restriction fragment length polymorphism. Approximately 10% of samples were randomly sequenced for each single nucleotide polymorphism to confirm the genotypes. The prediction of mRNA secondary structure for polymorphism FOXE3-p.Ala170Ala and PITX3-p.Ile95Ile was performed.Results:A significantly high frequency of T allele and a borderline significance in the frequency of TT genotype of FOXE3-p.Ala170Ala was observed in microphthalmia cases, as compared to controls [T allele: OR: [CI] = 1.8 [1.15-2.72], P = 0.0115; TT: OR [CI] = 2.9 [1.14-7.16], P = 0.0291). The frequency of CC genotype was significantly low in microphthalmia cases when compared to controls (CC: OR [CI] = 0.5 [0.24-0.86, P = 0.0150). There was no significant difference in the allele and genotype frequencies of PITX3-p.Ile95Ile between cases and controls. A slight free energy change was observed in the secondary structure of mRNA between the FOXE3-p.Ala170Ala C-allele (-917.60 kcal/mol) and T-allele (-916.80 kcal/mol) and between PITX3-p.Ile95Ile C-allele (-659.80 kcal/mol) and T-allele (-658.40 kcal/mol).Conclusion:The present findings indicate that FOXE3-p.Ala170Ala ‘T’ allele and ‘TT’ genotype could be predisposing factors for microphthalmia while ‘CC’ genotype might play a protective role against it. A reduction in the free energy change associated with FOXE3-p.Ala170Ala ‘T’ allele could further contribute towards disease risk.

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Unraveling the genetic cause of a consanguineous family with unilateral coloboma and retinoschisis: expanding the phenotypic variability of RAX mutations

Cited by 13 publications

References 27 publications

Truncating RAX Mutations: Anophthalmia, Hypopituitarism, Diabetes Insipidus, and Cleft Palate in Mice and Men

Truncating RAX Mutations: Anophthalmia, Hypopituitarism, Diabetes Insipidus, and Cleft Palate in Mice and Men

Genetics of anophthalmia and microphthalmia. Part 1: Non-syndromic anophthalmia/microphthalmia

Association of FOXE3-p.Ala170Ala and PITX3-p.Ile95Ile polymorphisms with congenital cataract and microphthalmia

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