Microphthalmia and anophthalmia (MA) are severe developmental eye anomalies, many of which are likely to have an underlying genetic cause. More than 30 genes have been described, each of which is ...responsible for a small percentage of these anomalies. Among these, is the FOXE3 gene, which was initially described in individuals with dominantly inherited anterior segment dysgenesis and, subsequently, associated with recessively inherited primary aphakia, sclerocornea and microphthalmia. In this work, we describe 8 individuals presenting with an MA phenotype. Among them, 7 are carrying biallelic recessive FOXE3 mutations and 2 of these have novel mutations: p.(Ala78Thr) and p.(Arg104Cys). The last of our patients is carrying in the heterozygous state the recessive p.(Arg90Leu) mutation in the FOXE3 gene. To further understand FOXE3 involvement in this wide spectrum of ocular anomalies with 2 different patterns of inheritance, we reviewed all individuals with ocular abnormalities described in the literature for which a FOXE3 mutation was identified. This review demonstrates that correlations exist between the mutation type, mode of inheritance and the phenotype severity. Furthermore, understanding the genetic basis of these conditions will contribute to overall understanding of eye development, improve the quality of care, genetic counseling and, in future, gene‐based therapies.
Phenotype and genotype of 123 patients (38 index cases and 85 family members) with a total of 20 different FOXE3 mutations
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
YAP1, which encodes the Yes-associated protein 1, is part of the Hippo pathway involved in development, growth, repair and homeostasis. Nonsense YAP1 mutations have been shown to co-segregate with ...autosomal dominantly inherited coloboma. Therefore, we screened YAP1 for variants in a cohort of 258 undiagnosed UK patients with developmental eye disorders, including anophthalmia, microphthalmia and coloboma. We identified a novel 1 bp deletion in YAP1 in a boy with bilateral microphthalmia and bilateral chorioretinal coloboma. This variant is located in the coding region of all nine YAP1 spliceforms, and results in a frameshift and subsequent premature termination codon in each. The variant is predicted to result in the loss of part of the transactivation domain of YAP1, and sequencing of cDNA from the patient shows it does not result in nonsense mediated decay. To investigate the role of YAP1 in human eye development, we performed in situ hybridisation utilising human embryonic tissue, and observed expression in the developing eye, neural tube, brain and kidney. These findings help confirm the role of YAP1 and the Hippo developmental pathway in human eye development and its associated anomalies and demonstrate its expression during development in affected organ systems.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background:Developmental eye anomalies, which include anophthalmia (absent eye) or microphthalmia (small eye) are an important cause of severe visual impairment in infants and young children. ...Heterozygous mutations in SOX2, a SOX1B-HMG box transcription factor, have been found in up to 10% of individuals with severe microphthalmia or anophthalmia and such mutations could also be associated with a range of non-ocular abnormalities.Methods:We performed mutation analysis on a new cohort of 120 patients with congenital eye abnormalities, mainly anophthalmia, microphthalmia and coloboma. Multiplex ligation-dependent probe amplification (MLPA) and fluorescence in situ hybridisation (FISH) were used to detect whole gene deletion.Results:We identified four novel intragenic SOX2 mutations (one single base deletion, one single base duplication and two point mutations generating premature translational termination codons) and two further cases with the previously reported c.70del20 mutation. Of 52 patients with severe microphthalmia or anophthalmia analysed by MLPA, 5 were found to be deleted for the whole SOX2 gene and 1 had a partial deletion. In two of these, FISH studies identified sub-microscopic deletions involving a minimum of 328 Kb and 550 Kb. The SOX2 phenotypes include a patient with anophthalmia, oesophageal abnormalities and horseshoe kidney, and a patient with a retinal dystrophy implicating SOX2 in retinal development.Conclusion:Our results provide further evidence that SOX2 haploinsufficiency is a common cause of severe developmental ocular malformations and that background genetic variation determines the varying phenotypes. Given the high incidence of whole gene deletion we recommend that all patients with severe microphthalmia or anophthalmia, including unilateral cases be screened by MLPA and FISH for SOX2 deletions.
MED12 is a subunit of the Mediator multiprotein complex with a central role in RNA polymerase II transcription and regulation of cell growth, development, and differentiation. This might underlie the ...variable phenotypes in males carrying missense variants in MED12, including X-linked recessive Ohdo, Lujan, and FG syndromes.
By international matchmaking we assembled variant and clinical data on 18 females presenting with variable neurodevelopmental disorders (NDDs) and harboring de novo variants in MED12.
Five nonsense variants clustered in the C-terminal region, two splice variants were found in the same exon 8 splice acceptor site, and 11 missense variants were distributed over the gene/protein. Protein truncating variants were associated with a severe, syndromic phenotype consisting of intellectual disability (ID), facial dysmorphism, short stature, skeletal abnormalities, feeding difficulties, and variable other abnormalities. De novo missense variants were associated with a less specific, but homogeneous phenotype including severe ID, autistic features, limited speech and variable other anomalies, overlapping both with females with truncating variants as well as males with missense variants.
We establish de novo truncating variants in MED12 as causative for a distinct NDD and de novo missense variants as causative for a severe, less specific NDD in females.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PDAC syndrome Pulmonary hypoplasia/agenesis, Diaphragmatic hernia/eventration, Anophthalmia/microphthalmia (A/M) and Cardiac Defect is a condition associated with recessive mutations in the STRA6 ...gene in some of these patients. Recently, cases with isolated anophthalmia have been associated with STRA6 mutations. To determine the minimal findings associated with STRA6 mutations, we performed mutation analysis of the STRA6 gene in 28 cases with anophthalmia. In 7 of the cases the anophthalmia was isolated, in 14 cases it was associated with one of the major features included in PDAC and 7 had other abnormalities. Mutations were identified in two individuals: one with bilateral anophthalmia and some features included in PDAC, who was a compound heterozygote for a missense mutation and a large intragenic deletion, and the second case with all the major features of PDAC and who had a homozygous splicing mutation. This study suggests that STRA6 mutations are more likely to be identified in individuals with A/M and other abnormalities included in the PDAC spectrum, rather than in isolated A/M cases.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Congenital anophthalmia and microphthalmia are rare developmental defects of the globe. They often arise in conjunction with other ocular defects such as coloboma and orbital cyst. They may also be ...part of more generalised syndromes, such as CHARGE syndrome. Anophthalmia, microphthalmia, and coloboma are likely to be caused by disturbances of the morphogenetic pathway that controls eye development, either as a result of primary genetic defect, or external gestational factors, including infection or drugs that can influence the smooth processes of morphogenesis. The ophthalmologist is often the primary carer for children with anophthalmia and microphthalmia, and as such can coordinate the multidisciplinary input needed to offer optimal care for these individuals, including vision and family support services. They are able to assess the vision and maximise the visual potential of the child and they can also ensure that the cosmetic and social impact of anophthalmia or microphthalmia is minimised by starting socket expansion or referring to a specialist oculoplastics and prosthetics unit. A coordinated approach with paediatrics is necessary to manage any associated conditions. Genetic diagnosis and investigations can greatly assist in providing a diagnosis and informed genetic counselling.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
8.
Genetics in microphthalmia Calvas, P.; Davis, E.; Ragge, N. ...
Acta ophthalmologica,
October 2016, 2016-10-00, 20161001, Volume:
94, Issue:
S256
Journal Article
Peer reviewed
Open access
Summary
Congenital malformations of the eye comprise a wide spectrum of developmental defects. Anophthalmia‐microphthalmia (AM) is the most severe end of these conditions. The different ocular ...malformations are thought to be part of an overlapping spectrum of embryonic developmental defects. Phenotypic overlap is emphasized by molecular results demonstrating that the same genes may lead to variable defects. We aimed at delineating the molecular bases of AM in order to improve knowledge on eye development as well as patient care. We follow one of the largest cohort of ocular developmental defects cases with extensive clinical and genetic analyses and report here extensive genetics analysis delineating a valuable genetic epidemiology of AM triggering genes. To date a genetic cause is identified in less than half of the patients suffering AM. The most likely explanation for this is that only a small proportion of causative genes have been identified. That is, we report here the strategy used to identify novel AM genes among rare and mainly sporadic patients. This led highlighting the malformation spectrum of already known genes and delineating original pathways respectively involved in retinoic acid metabolism and Sonic Hedgehog signalling.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
9.
Specific gene in microphthalmia Rozet, J.M.; Fares‐Taïe, L.; Chassaing, N. ...
Acta ophthalmologica,
October 2016, 2016-10-00, 20161001, Volume:
94, Issue:
S256
Journal Article
Peer reviewed
Open access
Summary
Anophthalmia and microphthalmia (A/M) are early‐eye‐development anomalies resulting in absent or small ocular globes, respectively. Genetically determined A/M are characterized by major ...genetic heterogeneity. In addition, there is a genetic overlap with some genes being involved in both anophthalmia and microphthalmia. Recently, we reported that mutations in the gene encoding the A3 isoform of the aldehyde dehydrogenase 1 (ALDH1A3) cause A/M with occasional orbital cystic, neurological, and cardiac anomalies in three consanguineous families. ALDH1A3 is a key enzyme in the formation of a retinoic acid (RA) gradient along the dorso‐ventral axis during early eye development. Although the role of (RA) signaling in eye development is well established, these findings provided genetic evidence of a direct link between RA‐synthesis dysfunction and early‐eye‐development anomalies. Since the original report, A/M has been ascribed to homozygous ALDH1A3 mutations in sixteen additional consanguineous families describing variable clinical expression, within and between families, ranging from silent expression to multisystemic diseases. The variable expression of ALDH1A3 mutations which are a leading cause of A/M will be discussed.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Aims: To study the management of the orbital cysts present in a group of patients with anophthalmos and microphthalmos. Methods: A retrospective study of 34 patients (40 orbits) treated for orbital ...cyst associated with microphthalmos and anophthalmos. Results: The two largest treatment groups comprised 17 orbits (42.5%) where the cyst was removed surgically and 17 orbits (42.5%) where the cyst was retained and conformers were used. The remaining cases comprised two orbits (5%) where the cyst was aspirated initially; two orbits (5%) with large cysts which will need to be excised after further orbital growth; one orbit (2.5%) in which a silicone expander was used initially, and one orbit (2.5%) in which a mildly microphthalmic eye had some vision and was monitored but required no surgery. Conclusion: In this study 33 out of 34 patients had a good cosmetic result which illustrates that the orbital cyst in microphthalmos or anophthalmos performs a useful role in socket expansion and that the majority of patients with this condition can expect a good cosmetic outcome.
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