RESUMO
Gestational vitamin A (retinol) deficiency poses a risk for ocular birth defects and blindness. We identified missense mutations in RBP4, encoding serum retinol binding protein, in three families with eye malformations of differing severity, including bilateral anophthalmia. The mutant phenotypes exhibit dominant inheritance, but incomplete penetrance. Maternal transmission significantly increases the probability of phenotypic expression. RBP normally delivers retinol from hepatic stores to peripheral tissues, including the placenta and fetal eye. The disease mutations greatly reduce retinol binding to RBP, yet paradoxically increase the affinity of RBP for its cell surface receptor, STRA6. By occupying STRA6 nonproductively, the dominant-negative proteins disrupt vitamin A delivery from wild-type proteins within the fetus, but also, in the case of maternal transmission, at the placenta. These findings establish a previously uncharacterized mode of maternal inheritance, distinct from imprinting and oocyte-derived mRNA, and define a group of hereditary disorders plausibly modulated by dietary vitamin A.
Assuntos
Oftalmopatias Hereditárias/genética , Mutação de Sentido Incorreto , Proteínas Plasmáticas de Ligação ao Retinol/genética , Sequência de Aminoácidos , Animais , Análise Mutacional de DNA , Feminino , Genes Dominantes , Humanos , Masculino , Troca Materno-Fetal , Dados de Sequência Molecular , Linhagem , Penetrância , Gravidez , Proteínas Plasmáticas de Ligação ao Retinol/química , Alinhamento de Sequência , Deficiência de Vitamina A/metabolismoRESUMO
The forkhead transcription factor FOXE3 is critical for vertebrate eye development. Recessive and dominant variants cause human ocular disease but the full range of phenotypes and mechanisms of action for the two classes of variants are unknown. We identified FOXE3 variants in individuals with congenital eye malformations and carried out in vitro functional analysis on selected alleles. Sixteen new recessive and dominant families, including six novel variants, were identified. Analysis of new and previously reported genetic and clinical data demonstrated a broad phenotypic range with an overlap between recessive and dominant disease. Most families with recessive alleles, composed of truncating and forkhead-domain missense variants, had severe corneal opacity (90%; sclerocornea in 47%), aphakia (83%) and microphthalmia (80%), but some had milder features including isolated cataract. The phenotype was most variable for recessive missense variants, suggesting that the functional consequences may be highly dependent on the type of amino acid substitution and its position. When assessed, aniridia or iris hypoplasia were noted in 89% and optic nerve anomalies in 60% of recessive cases, indicating that these defects are also common and may be underrecognized. In dominant pedigrees, caused by extension variants, normal eye size (96%), cataracts (99%) and variable anterior segment anomalies were seen in most, but some individuals had microphthalmia, aphakia or sclerocornea, more typical of recessive disease. Functional studies identified variable effects on the protein stability, DNA binding, nuclear localization and transcriptional activity for recessive FOXE3 variants, whereas dominant alleles showed severe impairment in all areas and dominant-negative characteristics.
Assuntos
Anormalidades do Olho/genética , Olho/embriologia , Fatores de Transcrição Forkhead/genética , Adolescente , Alelos , Catarata/genética , Criança , Opacidade da Córnea/genética , Deficiências do Desenvolvimento/genética , Olho/crescimento & desenvolvimento , Anormalidades do Olho/enzimologia , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Masculino , Mutação , Linhagem , FenótipoRESUMO
SOX2 pathogenic variants, though rare, constitute the most commonly known genetic cause of clinical anophthalmia and microphthalmia. However, patients without major ocular malformation, but with multi-system developmental disorders, have been reported, suggesting that the range of clinical phenotypes is broader than previously appreciated. We detail two patients with bilateral structurally normal eyes along with 11 other previously published patients. Our findings suggest that there is no obvious phenotypic or genotypic pattern that may help set apart patients with normal eyes. Our patients provide further evidence for broadening the phenotypic spectrum of SOX2 mutations and re-appraising the designation of SOX2 disorder as an anophthalmia/microphthalmia syndrome. We emphasize the importance of considering SOX2 pathogenic variants in the differential diagnoses of individuals with normal eyes, who may have varying combinations of features such as developmental delay, urogenital abnormalities, gastro-intestinal anomalies, pituitary dysfunction, midline structural anomalies, and complex movement disorders, seizures or other neurological issues.
Assuntos
Anoftalmia , Anormalidades do Olho , Microftalmia , Humanos , Anoftalmia/genética , Anoftalmia/patologia , Microftalmia/diagnóstico , Microftalmia/genética , Microftalmia/patologia , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Mutação , Fenótipo , Fatores de Transcrição SOXB1/genéticaRESUMO
The purpose of this article is to determine the cause of Leber congenital amaurosis (LCA) in Chuuk state, Federated States of Micronesia (FSM). In this prospective observational case series, five patients with early-onset vision loss were examined in Chuuk state, FSM, during an ocular genetics visit to study the elevated incidence of microphthalmia. Because of their low vision these patients were incorrectly assumed to have microphthalmia. A complete ophthalmological exam established a clinical diagnosis of LCA. Candidate gene exons were sequenced with a targeted retinal dystrophy panel. Five subjects in three related families were diagnosed with LCA. All five were from Tonoas Island, within the Chuuk Lagoon, with ages ranging from 6 months to 16 years. DNA sequencing of affected individuals revealed a homozygous CRB1 NM_201253.3:c.3134del pathogenic variant, which was heterozygous in their parents. CRB1 genotypes were confirmed by a PCR restriction assay. We report identification of a founder pathogenic variant in CRB1 responsible for autosomal recessive LCA in this isolated community. This discovery will lead to appropriate recurrence risk counseling.
Assuntos
Amaurose Congênita de Leber , Microftalmia , Humanos , Amaurose Congênita de Leber/genética , Mutação , Genótipo , Olho , Linhagem , Proteínas do Olho/genética , Análise Mutacional de DNA , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genéticaRESUMO
SOX2 variants and deletions are a common cause of anophthalmia and microphthalmia (A/M). This article presents data from a cohort of patients with SOX2 variants, some of whom have been followed for 20+ years. Medical records from patients enrolled in the A/M Research Registry and carrying SOX2 variants were reviewed. Thirty-seven patients were identified, ranging in age from infant to 30 years old. Eye anomalies were bilateral in 30 patients (81.1%), unilateral in 5 (13.5%), and absent in 2 (5.4%). Intellectual disability was present in all with data available and ranged from mild to profound. Seizures were noted in 18 of 27 (66.6%) patients, usually with abnormal brain MRIs (10/15, 66.7%). Growth issues were reported in 14 of 21 patients (66.7%) and 14 of 19 (73.7%) had gonadotropin deficiency. Genitourinary anomalies were seen in 15 of 19 (78.9%) male patients and 5 of 15 (33.3%) female patients. Patients with SOX2 nucleotide variants, whole gene deletions or translocations are typically affected with bilateral or unilateral microphthalmia and anophthalmia. Other associated features include intellectual disability, seizures, brain anomalies, growth hormone deficiency, gonadotropin deficiency, and genitourinary anomalies. Recommendations for newly diagnosed patients with SOX2 variants include eye exams, MRI of the brain and orbits, endocrine and neurology examinations. Since the clinical spectrum associated with SOX2 alleles has expanded beyond the originally reported phenotypes, we propose a broader term, SOX2-associated disorder, for this condition.
Assuntos
Anoftalmia , Microftalmia , Anoftalmia/genética , Anoftalmia/patologia , DNA , Feminino , Humanos , Masculino , Microftalmia/genética , Microftalmia/patologia , Sistema de Registros , Fatores de Transcrição SOXB1/genéticaRESUMO
OBJECTIVE: To determine the potential disease association between variants in LMBRD2 and complex multisystem neurological and developmental delay phenotypes. METHODS: Here we describe a series of de novo missense variants in LMBRD2 in 10 unrelated individuals with overlapping features. Exome sequencing or genome sequencing was performed on all individuals, and the cohort was assembled through GeneMatcher. RESULTS: LMBRD2 encodes an evolutionary ancient and widely expressed transmembrane protein with no known disease association, although two paralogues are involved in developmental and metabolic disorders. Exome or genome sequencing revealed rare de novo LMBRD2 missense variants in 10 individuals with developmental delay, intellectual disability, thin corpus callosum, microcephaly and seizures. We identified five unique variants and two recurrent variants, c.1448G>A (p.Arg483His) in three cases and c.367T>C (p.Trp123Arg) in two cases. All variants are absent from population allele frequency databases, and most are predicted to be deleterious by multiple in silico damage-prediction algorithms. CONCLUSION: These findings indicate that rare de novo variants in LMBRD2 can lead to a previously unrecognised early-onset neurodevelopmental disorder. Further investigation of individuals harbouring LMBRD2 variants may lead to a better understanding of the function of this ubiquitously expressed gene.
Assuntos
Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Transtornos das Habilidades Motoras/diagnóstico , Transtornos das Habilidades Motoras/genética , Mutação de Sentido Incorreto , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/genética , Proteínas de Transporte Nucleocitoplasmático/genética , Alelos , Substituição de Aminoácidos , Estudos de Coortes , Predisposição Genética para Doença , Genótipo , Humanos , FenótipoRESUMO
Complex microphthalmia is characterized by small eyes with additional abnormalities that may include anterior segment dysgenesis. While many genes are known, a genetic cause is identified in only 4-30% of microphthalmia, with the lowest rate in unilateral cases. We identified four novel pathogenic loss-of-function alleles in PRR12 in families affected by complex microphthalmia and/or Peters anomaly, including two de novo, the first dominantly transmitted allele, as well as the first splicing variant. The ocular phenotypes were isolated with no additional systemic features observed in two unrelated families. Remarkably, ocular phenotypes were asymmetric in all individuals and unilateral (with structurally normal contralateral eye) in three. There are only three previously reported PRR12 variants identified in probands with intellectual disability, neuropsychiatric disorders, and iris anomalies. While some overlap with previously reported cases is seen, nonsyndromic developmental ocular anomalies are a novel phenotype for this gene. Additional phenotypic expansions included short stature and normal development/cognition, each noted in two individuals in this cohort, as well as absence of neuropsychiatric disorders in all. This study identifies new associations for PRR12 disruption in humans and presents a genetic diagnosis resulting in unilateral ocular phenotypes in a significant proportion of cases.
Assuntos
Segmento Anterior do Olho/anormalidades , Opacidade da Córnea/genética , Anormalidades do Olho/genética , Variação Genética , Proteínas de Membrana/genética , Microftalmia/genética , Adolescente , Adulto , Alelos , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Mutação , Linhagem , FenótipoRESUMO
[This corrects the article DOI: 10.1371/journal.pgen.1002114.].
RESUMO
Microphthalmia, anophthalmia, and anterior segment dysgenesis are severe ocular developmental defects. There is a wide genetic heterogeneity leading to these ocular malformations. By using whole genome, exome and targeted sequencing in patients with ocular developmental anomalies, six biallelic pathogenic variants (including five novel variants) were identified in the PXDN gene in four families with microphthalmia and anterior segment dysgenesis. Only 11 different mutations (11 families) have been described in this gene to date. The phenotype of these patients is variable in severity, ranging from cataract and developmental glaucoma to complex microphthalmia. Interestingly, two unrelated patients of our series presented with an ocular phenotype including aniridia and microspherophakia. However, despite various phenotypic presentations and types of mutations, no genotype-phenotype correlation could be made. Thus, this work improves our knowledge of the recessive phenotype associated with biallelic variants in this gene and highlights the importance of screening PXDN in patients with anterior segment dysgenesis with or without microphthalmia.
Assuntos
Alelos , Anormalidades do Olho/genética , Microftalmia/genética , Mutação , Peroxidases/genética , Anormalidades do Olho/patologia , Feminino , Estudos de Associação Genética , Humanos , Masculino , Microftalmia/patologiaRESUMO
Steel syndrome was initially described by H. H. Steel in 1993 in Puerto Rico, at which time he described the clinical findings required for diagnosis. The responsible gene, COL27A1, was identified in 2015 (Gonzaga-Jauregui et al., European Journal of Human Genetics, 2015;23:342-346). Eleven patients have previously been described with Steel syndrome and homozygous COL27A1 mutations, with eight having an apparent founder mutation, p.Gly697Arg. We describe three more patients identified at Einstein Medical Center Philadelphia and St. Christopher's Hospital for Children (Philadelphia, PA) diagnosed with Steel syndrome. All three are of Puerto Rican ancestry with the previously described founder mutation and had either hip dislocations or hip dysplasia. Radial head dislocation was only identified in one patient while short stature and scoliosis were noted in two of these patients. There are now 51 patients in the literature with Steel syndrome, including the 3 patients in this article, and 14 patients with a genetically confirmed Steel syndrome diagnosis.
Assuntos
Colágenos Fibrilares/genética , Transtornos do Crescimento/patologia , Luxação do Quadril/patologia , Mutação , Escoliose/patologia , Adolescente , Criança , Feminino , Transtornos do Crescimento/genética , Luxação do Quadril/genética , Humanos , Lactente , Masculino , Philadelphia , Porto Rico , Escoliose/genéticaRESUMO
Retinoic acid (RA) signaling plays a key role in the development and function of several systems in mammals. We previously discovered that the de novo mutations c.1159C>T (p.Arg387Cys) and c.1159C>A (p.Arg387Ser) in the RA Receptor Beta (RARB) gene cause microphthalmia and diaphragmatic hernia. However, the natural history of affected subjects beyond the prenatal or neonatal period was unknown. Here, we describe nine additional subjects with microphthalmia who have de novo mutations in RARB, including the previously described p.Arg387Cys as well as the novel c.887G>C (p.Gly296Ala) and c.638T>C (p.Leu213Pro). Moreover, we review the information on four previously reported cases. All subjects who survived the neonatal period (n = 10) displayed severe global developmental delay with progressive motor impairment due to spasticity and/or dystonia (with or without chorea). The majority of subjects also showed Chiari type I malformation and severe feeding difficulties. We previously found that p.Arg387Cys and p.Arg387Ser induce a gain-of-function. We show here that the p.Gly296Ala and p.Leu213Pro RARB mutations further promote the RA ligand-induced transcriptional activity by twofold to threefold over the wild-type receptor, also indicating a gain-of-function mechanism. These observations suggest that precise regulation of RA signaling is required for brain development and/or function in humans.
Assuntos
Mutação com Ganho de Função , Deficiência Intelectual/genética , Transtornos dos Movimentos/genética , Receptores do Ácido Retinoico/genética , Adolescente , Criança , Pré-Escolar , Distúrbios Distônicos , Feminino , Humanos , Recém-Nascido , Masculino , Modelos Moleculares , Mutação de Sentido Incorreto , Conformação Proteica , Receptores do Ácido Retinoico/química , Ativação TranscricionalRESUMO
The major active retinoid, all-trans retinoic acid, has long been recognized as critical for the development of several organs, including the eye. Mutations in STRA6, the gene encoding the cellular receptor for vitamin A, in patients with Matthew-Wood syndrome and anophthalmia/microphthalmia (A/M), have previously demonstrated the importance of retinol metabolism in human eye disease. We used homozygosity mapping combined with next-generation sequencing to interrogate patients with anophthalmia and microphthalmia for new causative genes. We used whole-exome and whole-genome sequencing to study a family with two affected brothers with bilateral A/M and a simplex case with bilateral anophthalmia and hypoplasia of the optic nerve and optic chiasm. Analysis of novel sequence variants revealed homozygosity for two nonsense mutations in ALDH1A3, c.568A>G, predicting p.Lys190*, in the familial cases, and c.1165A>T, predicting p.Lys389*, in the simplex case. Both mutations predict nonsense-mediated decay and complete loss of function. We performed antisense morpholino (MO) studies in Danio rerio to characterize the developmental effects of loss of Aldh1a3 function. MO-injected larvae showed a significant reduction in eye size, and aberrant axonal projections to the tectum were noted. We conclude that ALDH1A3 loss of function causes anophthalmia and aberrant eye development in humans and in animal model systems.
Assuntos
Aldeído Oxirredutases/genética , Anoftalmia/genética , Códon sem Sentido/genética , Microftalmia/genética , Quiasma Óptico/anormalidades , Nervo Óptico/anormalidades , Aldeído Oxirredutases/metabolismo , Animais , Anoftalmia/metabolismo , Criança , Pré-Escolar , Exoma , Olho/crescimento & desenvolvimento , Olho/patologia , Feminino , Genoma , Homozigoto , Humanos , Lactente , Larva/genética , Larva/crescimento & desenvolvimento , Larva/metabolismo , Masculino , Microftalmia/metabolismo , Análise de Sequência de DNA , Análise de Sequência de RNA , Peixe-Zebra/embriologia , Peixe-Zebra/genéticaRESUMO
Ophthalmo-acromelic syndrome (OAS), also known as Waardenburg Anophthalmia syndrome, is defined by the combination of eye malformations, most commonly bilateral anophthalmia, with post-axial oligosyndactyly. Homozygosity mapping and subsequent targeted mutation analysis of a locus on 14q24.2 identified homozygous mutations in SMOC1 (SPARC-related modular calcium binding 1) in eight unrelated families. Four of these mutations are nonsense, two frame-shift, and two missense. The missense mutations are both in the second Thyroglobulin Type-1 (Tg1) domain of the protein. The orthologous gene in the mouse, Smoc1, shows site- and stage-specific expression during eye, limb, craniofacial, and somite development. We also report a targeted pre-conditional gene-trap mutation of Smoc1 (Smoc1(tm1a)) that reduces mRNA to â¼10% of wild-type levels. This gene-trap results in highly penetrant hindlimb post-axial oligosyndactyly in homozygous mutant animals (Smoc1(tm1a/tm1a)). Eye malformations, most commonly coloboma, and cleft palate occur in a significant proportion of Smoc1(tm1a/tm1a) embryos and pups. Thus partial loss of Smoc-1 results in a convincing phenocopy of the human disease. SMOC-1 is one of the two mammalian paralogs of Drosophila Pentagone, an inhibitor of decapentaplegic. The orthologous gene in Xenopus laevis, Smoc-1, also functions as a Bone Morphogenic Protein (BMP) antagonist in early embryogenesis. Loss of BMP antagonism during mammalian development provides a plausible explanation for both the limb and eye phenotype in humans and mice.
Assuntos
Anoftalmia/genética , Proteína Morfogenética Óssea 1/antagonistas & inibidores , Mutação , Osteonectina , Síndrome de Waardenburg/genética , Animais , Proteína Morfogenética Óssea 1/genética , Coloboma/genética , Análise Mutacional de DNA , Extremidades/crescimento & desenvolvimento , Olho/crescimento & desenvolvimento , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Osteonectina/genética , Osteonectina/metabolismo , Linhagem , Sindactilia/genética , Xenopus laevisRESUMO
For years, clinicians have offered gene-by-gene carrier screening to patients and couples considering future pregnancy or those with an ongoing pregnancy early in gestation. Examples include ethnic-specific screening offered to Ashkenazi Jewish patients and panethnic screening for cystic fibrosis and spinal muscular atrophy. Next-generation sequencing methods now available permit screening for many more disorders with high fidelity, quick turnaround time, and lower costs. However, instituting these technologies carries with it perils that must be addressed. The basis for the selection of disorders on expanded carrier screening panels should be disclosed. The information provided about disorders with mild phenotypes, variable expression, low penetrance, and/or characterized by an adult onset should be complete and transparent, allowing patients to opt out of receiving these test results. Patients also must be made aware of the concept of residual risk following negative test results. Laboratories have a duty to participate in and facilitate this information transfer.
Assuntos
Testes Genéticos , Heterozigoto , Diagnóstico Pré-Natal , Adulto , Feminino , Testes Genéticos/ética , Testes Genéticos/normas , Humanos , Guias de Prática Clínica como Assunto , Gravidez , Diagnóstico Pré-Natal/ética , Diagnóstico Pré-Natal/normasRESUMO
BACKGROUND: Holoprosencephaly (HPE), the most common malformation of the human forebrain, may result from mutations in over 12 genes. Sonic Hedgehog (SHH) was the first such gene discovered; mutations in SHH remain the most common cause of non-chromosomal HPE. The severity spectrum is wide, ranging from incompatibility with extrauterine life to isolated midline facial differences. OBJECTIVE: To characterise genetic and clinical findings in individuals with SHH mutations. METHODS: Through the National Institutes of Health and collaborating centres, DNA from approximately 2000 individuals with HPE spectrum disorders were analysed for SHH variations. Clinical details were examined and combined with published cases. RESULTS: This study describes 396 individuals, representing 157 unrelated kindreds, with SHH mutations; 141 (36%) have not been previously reported. SHH mutations more commonly resulted in non-HPE (64%) than frank HPE (36%), and non-HPE was significantly more common in patients with SHH than in those with mutations in the other common HPE related genes (p<0.0001 compared to ZIC2 or SIX3). Individuals with truncating mutations were significantly more likely to have frank HPE than those with non-truncating mutations (49% vs 35%, respectively; p=0.012). While mutations were significantly more common in the N-terminus than in the C-terminus (including accounting for the relative size of the coding regions, p=0.00010), no specific genotype-phenotype correlations could be established regarding mutation location. CONCLUSIONS: SHH mutations overall result in milder disease than mutations in other common HPE related genes. HPE is more frequent in individuals with truncating mutations, but clinical predictions at the individual level remain elusive.
Assuntos
Estudos de Associação Genética/métodos , Proteínas Hedgehog/genética , Holoprosencefalia/genética , Mutação , Feminino , Genótipo , Proteínas Hedgehog/metabolismo , Humanos , Masculino , Prosencéfalo/patologiaRESUMO
Lenz microphthalmia is inherited in an X-linked recessive pattern and comprises microphthalmia, mental retardation, and skeletal and other anomalies. Two loci associated with this syndrome, MAA (microphthalmia with associated anomalies) and MAA2, are situated respectively at Xq27-q28 (refs. 1,2) and Xp11.4-p21.2 (ref. 3). We identified a substitution, nt 254C-->T; P85L, in BCOR (encoding BCL-6-interacting corepressor, BCOR) in affected males from the family with Lenz syndrome previously used to identify the MAA2 locus. Oculofaciocardiodental syndrome (OFCD; OMIM 300166) is inherited in an X-linked dominant pattern with presumed male lethality and comprises microphthalmia, congenital cataracts, radiculomegaly, and cardiac and digital abnormalities. Given their phenotypic overlap, we proposed that OFCD and MAA2-associated Lenz microphthalmia were allelic, and we found different frameshift, deletion and nonsense mutations in BCOR in seven families affected with OFCD. Like wild-type BCOR, BCOR P85L and an OFCD-mutant form of BCOR can interact with BCL-6 and efficiently repress transcription. This indicates that these syndromes are likely to result from defects in alternative functions of BCOR, such as interactions with transcriptional partners other than BCL-6. We cloned the zebrafish (Danio rerio) ortholog of BCOR and found that knock-down of this ortholog caused developmental perturbations of the eye, skeleton and central nervous system consistent with the human syndromes, confirming that BCOR is a key transcriptional regulator during early embryogenesis.
Assuntos
Anormalidades Múltiplas/genética , Anormalidades do Olho/genética , Cardiopatias Congênitas/genética , Mutação , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Sequência de Aminoácidos , Animais , Mecanismo Genético de Compensação de Dose , Face/anormalidades , Humanos , Dados de Sequência Molecular , Proteínas Proto-Oncogênicas/química , Proteínas Repressoras/química , Homologia de Sequência de Aminoácidos , Síndrome , Anormalidades Dentárias/genética , Cromossomo X , Peixe-ZebraRESUMO
Histone lysine methyltransferase and demethylase enzymes play a central role in chromatin organization and gene expression through the dynamic regulation of histone lysine methylation. Consistent with this, genes encoding for histone lysine methyltransferases (KMTs) and demethylases (KDMs) are involved in complex human syndromes, termed congenital regulopathies. In this report, we present several lines of evidence for the involvement of these genes in developmental ocular phenotypes, suggesting that individuals with structural eye defects, especially when accompanied by craniofacial, neurodevelopmental and growth abnormalities, should be examined for possible variants in these genes. We identified nine heterozygous damaging genetic variants in KMT2D (5) and four other histone lysine methyltransferases/demethylases (KMT2C, SETD1A/KMT2F, KDM6A and KDM5C) in unrelated families affected with developmental eye disease, such as Peters anomaly, sclerocornea, Axenfeld-Rieger spectrum, microphthalmia and coloboma. Two families were clinically diagnosed with Axenfeld-Rieger syndrome and two were diagnosed with Peters plus-like syndrome; others received no specific diagnosis prior to genetic testing. All nine alleles were novel and five of them occurred de novo; five variants resulted in premature truncation, three were missense changes and one was an in-frame deletion/insertion; and seven variants were categorized as pathogenic or likely pathogenic and two were variants of uncertain significance. This study expands the phenotypic spectra associated with KMT and KDM factors and highlights the importance of genetic testing for correct clinical diagnosis.
Assuntos
Anormalidades do Olho , Histonas , Humanos , Histonas/genética , Lisina/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Anormalidades do Olho/genética , Histona Desmetilases/genética , Histona Desmetilases/metabolismoRESUMO
ARHGAP35 has known roles in cell migration, invasion and division, neuronal morphogenesis, and gene/mRNA regulation; prior studies indicate a role in cancer in humans and in the developing eyes, neural tissue, and renal structures in mice. We identified damaging variants in ARHGAP35 in five individuals from four families affected with anophthalmia, microphthalmia, coloboma and/or anterior segment dysgenesis disorders, together with variable non-ocular phenotypes in some families including renal, neurological, or cardiac anomalies. Three variants affected the extreme C-terminus of the protein, with two resulting in a frameshift and C-terminal extension and the other a missense change in the Rho-GAP domain; the fourth (nonsense) variant affected the middle of the gene and is the only allele predicted to undergo nonsense-mediated decay. This study implicates ARHGAP35 in human developmental eye phenotypes. C-terminal clustering of the identified alleles indicates a possible common mechanism for ocular disease but requires further studies.
Assuntos
Anoftalmia , Coloboma , Anormalidades do Olho , Microftalmia , Humanos , Animais , Camundongos , Anormalidades do Olho/genética , Microftalmia/genética , Anoftalmia/genética , Coloboma/genética , Fenótipo , Mutação , Proteínas Repressoras/genética , Fatores de Troca do Nucleotídeo Guanina/genéticaRESUMO
Vax1 and Vax2 have been implicated in eye development and the closure of the choroid fissure in mice and zebrafish. We sequenced the coding exons of VAX1 and VAX2 in 70 patients with anophthalmia/microphthalmia (A/M). In VAX1, we observed homozygosity for two successive nucleotide substitutions c.453G>A and c.454C>A, predicting p.Arg152Ser, in a proband of Egyptian origin with microphthalmia, small optic nerves, cleft lip/palate, and corpus callosum agenesis. This mutation affects an invariant residue in the homeodomain of VAX1 and was absent from 96 Egyptian controls. It is likely that the mutation results in a loss of function, as the mutation results in a phenotype similar to the Vax1 homozygous null mouse. We did not identify any mutations in VAX2. This is the first description of a phenotype associated with a VAX1 mutation in humans and establishes VAX1 as a new causative gene for A/M.
Assuntos
Agenesia do Corpo Caloso/genética , Fenda Labial/genética , Fissura Palatina/genética , Proteínas de Homeodomínio/genética , Microftalmia/genética , Mutação , Fenótipo , Fatores de Transcrição/genética , Substituição de Aminoácidos , Pré-Escolar , Éxons , Frequência do Gene , Células HEK293 , Homozigoto , Humanos , MasculinoRESUMO
BMP4 loss-of-function mutations and deletions have been shown to be associated with ocular, digital, and brain anomalies, but due to the paucity of these reports, the full phenotypic spectrum of human BMP4 mutations is not clear. We screened 133 patients with a variety of ocular disorders for BMP4 coding region mutations or genomic deletions. BMP4 deletions were detected in two patients: a patient affected with SHORT syndrome and a patient with anterior segment anomalies along with craniofacial dysmorphism and cognitive impairment. In addition to this, three intragenic BMP4 mutations were identified. A patient with anophthalmia, microphthalmia with sclerocornea, right-sided diaphragmatic hernia, and hydrocephalus was found to have a c.592C >T (p.R198X) nonsense mutation in BMP4. A frameshift mutation, c.171dupC (p.E58RfsX17), was identified in two half-siblings with anophthalmia/microphthalmia, discordant developmental delay/postaxial polydactyly, and poor growth as well as their unaffected mother; one affected sibling carried an additional BMP4 mutation in the second allele, c.362A > G (p.H121R). This is the first report indicating a role for BMP4 in SHORT syndrome, Axenfeld-Rieger malformation, growth delay, macrocephaly, and diaphragmatic hernia. These results significantly expand the number of reported loss-of-function mutations, further support the critical role of BMP4 in ocular development, and provide additional evidence of variable expression/non-penetrance of BMP4 mutations.