Dr Dorine Bax
PhD
Research Co-ordinator
School of Biological and Medical Sciences
Role
My role involves looking after the families taking part in 'The Genetics Of Eye and Brain Anomalies Study'' (PI Professor Nicola Ragge) on a day-to-day basis, as well as coordinating various aspects of the team's research
Research
Publications
Journal articles
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Ceroni F, Cicekdal MB, Holt R, Sorokina E, Chassaing N, Clokie S, Naert T, Talbot LV, Muheisen S, Bax DA, Kesim Y, Kivuva EC, Vincent-Delorme C, Lienkamp SS, Plaisancie J, De Baere E, Calvas P, Vleminckx K, Semina EV, Ragge NK, 'Deletion upstream of MAB21L2 highlights the importance of evolutionarily conserved non-coding sequences for eye development'
Nature Communications (2024)
ISSN: 2041-1723 eISSN: 2041-1723AbstractAnophthalmia, microphthalmia and coloboma (AMC) comprise a spectrum of developmental eye disorders, accounting for approximately 20% of childhood visual impairment. While non-coding regulatory sequences are increasingly recognised as contributing to disease burden, characterising their impact on gene function and phenotype remains challenging. Furthermore, little is known of the nature and extent of their contribution to AMC phenotypes. We report two families with variants in or near MAB21L2, a gene where genetic variants are known to cause AMC in humans and animal models. The first proband, presenting with microphthalmia and coloboma, has a likely pathogenic missense variant (c.338G>C; p.[Trp113Ser]), segregating within the family. The second individual, presenting with microphthalmia, carries an ~113.5kb homozygous deletion 19.38kb upstream of MAB21L2. Modelling of the deletion results in transient small lens and coloboma as well as midbrain anomalies in zebrafish, and microphthalmia and coloboma in Xenopus tropicalis. Using conservation analysis, we identify 15 non-coding conserved elements (CEs) within the deleted region, while ChIP-seq data from mouse embryonic stem cells demonstrates that two of these (CE13 and 14) bind Otx2, a protein with an established role in eye development. Targeted disruption of CE14 in Xenopus tropicalis recapitulates an ocular coloboma phenotype, supporting its role in eye development. Together, our data provides insights into regulatory mechanisms underlying eye development and highlights the importance of non-coding sequences as a source of genetic diagnoses in AMC.
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Plaisancié J, Jelena Martinovic J, Chesneau B, Whalen S, Rodriguez D, Audebert-Bellanger S, Marzin P, Grotto S, Perthus I, Holt R, Bax D, Ragge NK, Chassaing N, 'Clinical, genetic and biochemical signatures of RBP4-related ocular malformations'
Journal of Medical Genetics 61 (1) (2023) pp.84-92
ISSN: 0022-2593 eISSN: 1468-6244AbstractPublished here Open Access on RADARBackground: The retinoic acid (RA) pathway plays a crucial role in both eye morphogenesis and the visual cycle. Individuals with mono- and bi-allelic pathogenic variants in RBP4, encoding a serum retinol specific transporter, display variable ocular phenotypes. Although few families have been reported worldwide, recessive inherited variants appear to be associated with retinal degeneration, while individuals with dominantly inherited variants manifest ocular development anomalies, mainly microphthalmia, anophthalmia and coloboma (MAC).
Method: We report here 7 new families (13 patients) with isolated and syndromic MAC harbouring heterozygous RBP4 variants, to whom we performed biochemical analyses.
Results: For the first time, malformations that overlap the clinical spectrum of vitamin A deficiency are reported, providing a link with other RA disorders. Our data support two distinct phenotypes depending on the nature and mode of inheritance of the variants: dominantly inherited, almost exclusively missense, associated with ocular malformations, in contrast to recessive, mainly truncating, associated with retinal degeneration. Moreover, we also confirm the skewed inheritance and impact of maternal RBP4 genotypes on phenotypic expression in dominant forms suggesting that maternal RBP4 genetic status and content of diet during pregnancy may modify MAC occurrence and severity. Furthermore, we demonstrate that RBP blood dosage in patients could provide a biological signature crucial for classifying RBP4 variants. Finally, we propose a novel hypothesis to explain the mechanisms underlying the observed genotype-phenotype correlations in RBP4 mutational spectrum.
Conclusion: Dominant missense variants in RBP4 are associated with MAC of incomplete penetrance with maternal inheritance through a likely dominant-negative mechanism.
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Kesim Y, Ceroni F, Damián A, Blanco-Kelly F , Ayuso C, Williamson K, Paquis V, Bax DA, Plaisancié J, Rieubland C, Chamlal M, Cortón M, Chassaing N, Calvas P, Ragge NK, 'Clinical and genetic analysis further delineates the phenotypic spectrum of ALDH1A3-related anophthalmia and microphthalmia'
European Journal of Human Genetics 31 (2023) pp.1175-1180
ISSN: 1018-4813 eISSN: 1476-5438AbstractPublished here Open Access on RADARBiallelic pathogenic variants in ALDH1A3 are responsible for approximately 11% of recessively inherited cases of severe developmental eye anomalies. Some individuals can display variable neurodevelopmental features, but the relationship to the ALDH1A3 variants remains unclear. Here, we describe seven unrelated families with biallelic pathogenic ALDH1A3 variants: four compound heterozygous and three homozygous. All affected individuals had bilateral anophthalmia/microphthalmia (A/M), three with additional intellectual or developmental delay, one with autism and seizures and three with facial dysmorphic features. This study confirms that individuals with biallelic pathogenic ALDH1A3 variants consistently manifest A/M, but additionally display neurodevelopmental features with significant intra- and inter-familial variability. Furthermore, we describe the first case with cataract and highlight the importance of screening ALDH1A3 variants in nonconsanguineous families with A/M.
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Holt R, Goudie D, Damián A, Gardham A, Ramond F, Putoux A, Sarkar A, Clowes V, Clayton-Smith J, Banka S, Cortazar Galarza L, Thuret G, Ubeda Erviti M, Zurutuza Ibarguren A, Saez Villaverde R, Tamayo Duran A, Ayuso C, Bax DA, Plaisancie J, Corton M, Chassaing N, Calvas P, Ragge NK
, 'Individuals with heterozygous variants in the Wnt-signalling pathway gene FZD5 delineate a phenotype characterized by isolated coloboma and variable expressivity'
Ophthalmic Genetics 43 (6) (2022) pp.809-816
ISSN: 1381-6810 eISSN: 1744-5094AbstractPublished here Open Access on RADARBackground: Anophthalmia, microphthalmia and coloboma are a genetically heterogenous spectrum of developmental eye disorders. Recently, variants in the Wnt-pathway gene Frizzled Class Receptor 5 (FZD5) have been identified in individuals with coloboma and rarely microphthalmia, sometimes with additional phenotypes and variable penetrance. Materials and Methods: We identified variants in FZD5 in individuals with developmental eye disorders from the UK (including the DDD Study [www.ddduk.org/access.html]), France and Spain using whole genome/exome sequencing or customized NGS panels of ocular development genes. Results: We report eight new families with FZD5 variants and ocular coloboma. Three individuals presented with additional syndromic features, two explicable by additional variants in other genes (SLC12A2 and DDX3X). In two families initially showing incomplete penetrance, re-examination of apparently unaffected carrier individuals revealed subtle ocular colobomatous phenotypes. Finally, we report two families with microphthalmia in addition to coloboma, representing the second and third reported cases of this phenotype in conjunction with FZD5 variants. Conclusions: Our findings indicate FZD5 variants are typically associated with isolated ocular coloboma, occasionally microphthalmia, and that extraocular phenotypes are likely to be explained by other gene alterations.
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Ceroni F, Osborne D, Clokie S, Bax DA, Cassidy EJ, Dunn MJ, Harris C, Self JE, Ragge NK, 'Analysis of Fibroblast Growth Factor 14 (FGF14) structural variants reveals the genetic basis of the early onset nystagmus locus NYS4 and variable ataxia'
European Journal of Human Genetics 31 (2022) pp.353-359
ISSN: 1018-4813 eISSN: 1476-5438AbstractPublished here Open Access on RADARNystagmus (involuntary, rhythmical eye movements) can arise due to sensory eye defects, in association with neurological disorders or as an isolated condition. We identified a family with early onset nystagmus and additional neurological features carrying a partial duplication of FGF14, a gene associated with spinocerebellar ataxia type 27 (SCA27) and episodic ataxia. Detailed eye movement analysis revealed oculomotor anomalies strikingly similar to those reported in a previously described four-generation family with early onset nystagmus and linkage to a region on chromosome 13q31.3-q33.1 (NYS4). Since FGF14 lies within NYS4, we revisited the original pedigree using whole genome sequencing, identifying a 161kb heterozygous deletion disrupting FGF14 and ITGBL1 in the affected individuals, suggesting an FGF14-related condition. Therefore, our study reveals the genetic variant underlying NYS4, expands the spectrum of pathogenic FGF14 variants, and highlights the importance of screening FGF14 in apparently isolated early onset nystagmus.
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Holt RJ, Young RM, Crespo B, Ceroni F, Curry CJ, Bellacchio E, Bax DA, Ciolfi A, Simon M, Fagerberg CR, van Binsbergen E, De Luca A, Memo L, Dobyns WB, Mohammed AA, Clokie SJH, Zazo Seco C, Jiang YH, Sørensen KP, Andersen H, Sullivan J, Powis Z, Chassevent A, Smith-Hicks C, Petrovski S, Antoniadi T, Shashi V, Gelb B,Wilson SW,
Gerrelli D, Tartaglia M, Chassaing N, Calvas P, Ragge NK, 'De novo missense variants in FBXW11 cause diverse developmental phenotypes including brain, eye and digit anomalies'
American Journal of Human Genetics 105 (3) (2019) pp.P640-P657
ISSN: 0002-9297 eISSN: 1537-6605AbstractPublished here Open Access on RADARThe identification of genetic variants implicated in human developmental disorders has been revolutionized by second-generation sequencing combined with international pooling of cases. Here, we describe seven individuals who have diverse yet overlapping developmental anomalies, and who all have de novo missense FBXW11 variants identified by whole exome or whole genome sequencing and not reported in the gnomAD database. Their phenotypes include striking neurodevelopmental, digital, jaw, and eye anomalies, and in one individual, features resembling Noonan syndrome, a condition caused by dysregulated RAS signaling. FBXW11 encodes an F-box protein, part of the Skp1-cullin-F-box (SCF) ubiquitin ligase complex, involved in ubiquitination and proteasomal degradation and thus fundamental to many protein regulatory processes. FBXW11 targets include b-catenin and GLI transcription factors, key mediators of Wnt and Hh signaling, respectively, critical to digital, neurological, and eye development. Structural analyses indicate affected residues cluster at the surface of the loops of the substrate-binding domain of FBXW11, and the variants are predicted to destabilize the protein and/or its interactions. In situ hybridization studies on human and zebrafish embryonic tissues demonstrate FBXW11 is expressed in the developing eye, brain, mandibular processes, and limb buds or pectoral fins. Knockdown of the zebrafish FBXW11 orthologs fbxw11a and fbxw11b resulted in embryos with smaller, misshapen, and underdeveloped eyes and abnormal jaw and pectoral fin development. Our findings support the role of FBXW11 in multiple developmental processes, including those involving the brain, eye, digits, and jaw.
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Ragge N, Isidor B, Bitoun P, Odent S, Giurgea I, Cogné B, Deb W, Vincent M, Le Gall J, Morton J, Lim D; DDD Study, Le Meur G, Zazo Seco C, Zafeiropoulou D, Bax D, Zwijnenburg P, Arteche A, Swafiri ST, Cleaver R, McEntagart M, Kini U, Newman W, Ayuso C, Corton M, Herenger Y, Jeanne M, Calvas P, Chassaing N., 'Expanding the phenotype of the X-linked BCOR microphthalmia syndromes'
Human Genetics 138 (2018) pp.1051-1069
ISSN: 0340-6717 eISSN: 1432-1203AbstractTwo distinct syndromes arise from pathogenic variants in the X-linked gene BCOR (BCL-6 corepressor): oculofaciocardiodental (OFCD) syndrome, which affects females, and a severe microphthalmia (‘Lenz’-type) syndrome affecting males. OFCD is an X-linked dominant syndrome caused by a variety of BCOR null mutations. As it manifests only in females, it is presumed to be lethal in males. The severe male X-linked recessive microphthalmia syndrome (‘Lenz’) usually includes developmental delay in addition to the eye findings and is caused by hypomorphic BCOR variants, mainly by a specific missense variant c.254C > T, p.(Pro85Leu). Here, we detail 16 new cases (11 females with 4 additional, genetically confirmed, affected female relatives; 5 male cases each with unaffected carrier mothers). We describe new variants and broaden the phenotypic description for OFCD to include neuropathy, muscle hypotonia, pituitary underdevelopment, brain atrophy, lipoma and the first description of childhood lymphoma in an OFCD case. Our male X-linked recessive cases show significant new phenotypes: developmental delay (without eye anomalies) in two affected half-brothers with a novel BCOR variant, and one male with high myopia, megalophthalmos, posterior embryotoxon, developmental delay, and heart and bony anomalies with a previously undescribed BCOR splice site variant. Our female OFCD cases and their affected female relatives showed variable features, but consistently had early onset cataracts. We show that a mosaic carrier mother manifested early cataract and dental anomalies. All female carriers of the male X-linked recessive cases for whom genetic confirmation was available showed skewed X-inactivation and were unaffected. In view of the extended phenotype, we suggest a new term of X-linked BCOR-related syndrome.Published here Open Access on RADAR -
Ceroni F, Aguilera-Garcia D, Chassaing N, Bax DA, Blanco-Kelly F, Ramos P, Tarilonte M, Villaverde C, da Silva LRJ, Ballesta-Martínez MJ, Sanchez-Soler MJ, Holt RJ, Cooper-Charles L, Bruty J, Wallis Y, McMullan D, Hoffman J, Bunyan D, Stewart A, Stewart H, Lachlan K; DDD Study, Fryer A, McKay V, Roume J, Dureau P, Saggar A, Griffiths M, Calvas P, Ayuso C, Corton M, Ragge NK., 'New GJA8 variants and phenotypes highlight its critical role in a broad spectrum of eye anomalies'
Human Genetics 138 (8/9) (2018) pp.1027-1042
ISSN: 0340-6717 eISSN: 1432-1203AbstractGJA8 encodes connexin 50 (Cx50), a transmembrane protein involved in the formation of lens gap junctions. GJA8 mutations have been linked to early onset cataracts in humans and animal models. In mice, missense mutations and homozygous Gja8 deletions lead to smaller lenses and microphthalmia in addition to cataract, suggesting that Gja8 may play a role in both lens development and ocular growth. Following screening of GJA8 in a cohort of 426 individuals with severe congenital eye anomalies, primarily anophthalmia, microphthalmia and coloboma, we identified four known [p.(Thr39Arg), p.(Trp45Leu), p.(Asp51Asn), and p.(Gly94Arg)] and two novel [p.(Phe70Leu) and p.(Val97Gly)] likely pathogenic variants in seven families. Five of these co-segregated with cataracts and microphthalmia, whereas the variant p.(Gly94Arg) was identified in an individual with congenital aphakia, sclerocornea, microphthalmia and coloboma. Four missense variants of unknown or unlikely clinical significance were also identified. Furthermore, the screening of GJA8 structural variants in a subgroup of 188 individuals identified heterozygous 1q21 microdeletions in five families with coloboma and other ocular and/or extraocular findings. However, the exact genotype–phenotype correlation of these structural variants remains to be established. Our data expand the spectrum of GJA8 variants and associated phenotypes, confirming the importance of this gene in early eye development.Published here Open Access on RADAR -
Holt R, Ceroni F, Bax DA, Broadgate S, Diaz DG, Santos C, Gerrelli D, Ragge NK, 'New variant and expression studies provide further insight into the genotype-phenotype correlation in YAP1-related developmental eye disorders'
Scientific Reports 7 (2017)
ISSN: 2045-2322AbstractYAP1, which encodes the Yes-associated protein 1, is part of the Hippo pathway involved inPublished here Open Access on RADAR
development, growth, repair and homeostasis. Nonsense YAP1 mutations have been shown to cosegregate 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 identifed a novel 1bp 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 fndings help confrm the role of YAP1 and the Hippo developmental pathway in human eye development and its associated anomalies and demonstrate its expression during development in afected organ systems. -
Holt R, Ugur Iseri SA, Wyatt AW, Bax DA, Gold Diaz D, Santos C, Broadgate S, Dunn R, Bruty J, Wallis Y, McMullan D, Ogilvie C, Gerrelli D, Zhang Y, Ragge NK, 'Identification and functional characterisation of genetic variants in OLFM2 in children with developmental eye disorders'
Human Genetics 136 (1) (2016) pp.119-127
ISSN: 0340-6717 eISSN: 1432-1203AbstractAnophthalmia, microphthalmia, and coloboma are a genetically heterogeneous spectrum of developmental eye disorders and affect around 30 per 100,000 live births. OLFM2 encodes a secreted glycoprotein belonging to the noelin family of olfactomedin domain-containing proteins that modulate the timing of neuronal differentiation during development. OLFM2 SNPs have been associated with open angle glaucoma in a case–control study, and knockdown of Olfm2 in zebrafish results in reduced eye size. From a cohort of 258 individuals with developmental eye anomalies, we identified two with heterozygous variants in OLFM2: an individual with bilateral microphthalmia carrying a de novo 19p13.2 microdeletion involving OLFM2 and a second individual with unilateral microphthalmia and contralateral coloboma who had a novel single base change in the 5′ untranslated region. Dual luciferase assays demonstrated that the latter variant causes a significant decrease in expression of OLFM2. Furthermore, RNA in situ hybridisation experiments using human developmental tissue revealed expression in relevant structures, including the lens vesicle and optic cup. Our study indicates that OLFM2 is likely to be important in mammalian eye development and disease and should be considered as a gene for human ocular anomalies.Published here Open Access on RADAR