RESUMO
PURPOSE: To describe our experience with a large cohort (411 patients from 288 families) of various forms of skeletal dysplasia who were molecularly characterized. METHODS: Detailed phenotyping and next-generation sequencing (panel and exome). RESULTS: Our analysis revealed 224 pathogenic/likely pathogenic variants (54 (24%) of which are novel) in 123 genes with established or tentative links to skeletal dysplasia. In addition, we propose 5 genes as candidate disease genes with suggestive biological links (WNT3A, SUCO, RIN1, DIP2C, and PAN2). Phenotypically, we note that our cohort spans 36 established phenotypic categories by the International Skeletal Dysplasia Nosology, as well as 18 novel skeletal dysplasia phenotypes that could not be classified under these categories, e.g., the novel C3orf17-related skeletal dysplasia. We also describe novel phenotypic aspects of well-known disease genes, e.g., PGAP3-related Toriello-Carey syndrome-like phenotype. We note a strong founder effect for many genes in our cohort, which allowed us to calculate a minimum disease burden for the autosomal recessive forms of skeletal dysplasia in our population (7.16E-04), which is much higher than the global average. CONCLUSION: By expanding the phenotypic, allelic, and locus heterogeneity of skeletal dysplasia in humans, we hope our study will improve the diagnostic rate of patients with these conditions.
Assuntos
Exoma/genética , Heterogeneidade Genética , Predisposição Genética para Doença , Anormalidades Musculoesqueléticas/genética , Alelos , Proteínas Sanguíneas/genética , Hidrolases de Éster Carboxílico , Estudos de Coortes , Exorribonucleases/genética , Feminino , Proteínas Fetais/genética , Efeito Fundador , Genética Populacional , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Proteínas de Membrana/genética , Anormalidades Musculoesqueléticas/classificação , Anormalidades Musculoesqueléticas/patologia , Proteínas de Neoplasias/genética , Proteínas Oncogênicas/genética , Fenótipo , Receptores de Superfície Celular/genética , Proteína Wnt3A/genéticaRESUMO
We have previously described a syndrome characterized by facial dysmorphism, lens dislocation, anterior-segment abnormalities, and spontaneous filtering blebs (FDLAB, or Traboulsi syndrome). In view of the consanguineous nature of the affected families and the likely autosomal-recessive inheritance pattern of this syndrome, we undertook autozygosity mapping and whole-exome sequencing to identify ASPH as the disease locus, in which we identified two homozygous mutations. ASPH encodes aspartyl/asparaginyl ß-hydroxylase (ASPH), which has been found to hydroxylate aspartic acid and asparagine residues on epidermal growth factor (EGF)-domain-containing proteins. The truncating and missense mutations we identified are predicted to severely impair the enzymatic function of ASPH, which suggests a possible link to other forms of ectopia lentis given that many of the genes implicated in this phenotype encode proteins that harbor EGF domains. Developmental analysis of Asph revealed an expression pattern consistent with the proposed link to the human syndrome. Indeed, Asph-knockout mice had a foreshortened snout, which corresponds to the facial abnormalities in individuals with Traboulsi syndrome. These data support a genetic basis for a syndromic form of ectopia lentis and the role of aspartyl hydroxylation in human development.
Assuntos
Segmento Anterior do Olho/anormalidades , Proteínas de Ligação ao Cálcio/genética , Anormalidades Craniofaciais/genética , Ectopia do Cristalino/genética , Iris/anormalidades , Proteínas de Membrana/genética , Oxigenases de Função Mista/genética , Proteínas Musculares/genética , Sequência de Aminoácidos , Animais , Segmento Anterior do Olho/enzimologia , Anormalidades Craniofaciais/enzimologia , Análise Mutacional de DNA , Ectopia do Cristalino/enzimologia , Fator de Crescimento Epidérmico/química , Exoma/genética , Feminino , Humanos , Iris/enzimologia , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Linhagem , Estrutura Terciária de Proteína/genética , Síndrome , Adulto JovemRESUMO
Klippel-Feil syndrome (KFS) is a segmentation malformation of the cervical spine; clinically, it manifests as a short neck with reduced mobility and a low posterior hairline. Several genes have been proposed as candidates for KFS when it is present with other associated anomalies, but the genetics of isolated KFS have been difficult to study because of the syndrome's mostly sporadic occurrence. We describe a multiplex consanguineous family in which isolated KFS maps to a single 17q21.31 locus that harbors a homozygous frameshift deletion in MEOX1; this deletion results in complete instability of the transcript. Direct sequencing of this gene in two siblings from another consanguineous family affected by isolated KFS uncovered another homozygous truncating (nonsense) MEOX1 mutation that also leads to complete degradation of the transcript. This gene encodes a transcription factor with a well-established and nonredundant role in somite development, and homozygous null alleles of Meox1 in mice have a cervical skeletal defect that is remarkably similar to the one we observe in human individuals with MEOX1 mutations. Our data strongly suggest that KFS is the human phenotypic equivalent of the sclerotome polarity defect that results from Meox1 deficiency in mice.
Assuntos
Síndrome de Klippel-Feil/genética , Fatores de Transcrição/genética , Criança , Feminino , Genes Recessivos , Proteínas de Homeodomínio , Humanos , Masculino , MutaçãoRESUMO
Myopia is an extremely common eye disorder but the pathogenesis of its isolated form, which accounts for the overwhelming majority of cases, remains poorly understood. There is strong evidence for genetic predisposition to myopia, but determining myopia genetic risk factors has been difficult to achieve. We have identified Mendelian forms of myopia in four consanguineous families and implemented exome/autozygome analysis to identify homozygous truncating variants in LRPAP1 and CTSH as the likely causal mutations. LRPAP1 encodes a chaperone of LRP1, which is known to influence TGF-ß activity. Interestingly, we observed marked deficiency of LRP1 and upregulation of TGF-ß in cells from affected individuals, the latter being consistent with available data on the role of TGF-ß in the remodeling of the sclera in myopia and the high frequency of myopia in individuals with Marfan syndrome who characteristically have upregulation of TGF-ß signaling. CTSH, on the other hand, encodes a protease and we show that deficiency of the murine ortholog results in markedly abnormal globes consistent with the observed human phenotype. Our data highlight a role for LRPAP1 and CTSH in myopia genetics and demonstrate the power of Mendelian forms in illuminating new molecular mechanisms that may be relevant to common phenotypes.
Assuntos
Catepsina H/genética , Proteína Associada a Proteínas Relacionadas a Receptor de LDL/genética , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Síndrome de Marfan/genética , Mutação , Miopia/genética , Fator de Crescimento Transformador beta/genética , Adolescente , Animais , Catepsina H/metabolismo , Criança , Pré-Escolar , Feminino , Expressão Gênica , Predisposição Genética para Doença , Homozigoto , Humanos , Lactente , Proteína Associada a Proteínas Relacionadas a Receptor de LDL/metabolismo , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Síndrome de Marfan/metabolismo , Síndrome de Marfan/patologia , Camundongos , Miopia/metabolismo , Miopia/patologia , Linhagem , Fenótipo , Esclera/metabolismo , Esclera/patologia , Índice de Gravidade de Doença , Fator de Crescimento Transformador beta/metabolismoRESUMO
BACKGROUND: Klippel-Feil anomaly (KFA) can be seen in a number of syndromes. We describe an apparently novel syndromic association with KFA. METHODS: Clinical phenotyping of two consanguineous families followed by combined autozygome/exome analysis. RESULTS: Two patients from two apparently unrelated families shared a strikingly similar phenotype characterised by KFA, myopathy, mild short stature, microcephaly, and distinctive facies. They shared a single founder autozygous interval in which whole exome sequencing revealed a truncating mutation in MYO18B. There was virtually complete loss of the transcript in peripheral blood, indicative of nonsense-mediated decay. Electron microscopy of muscle confirms abnormal myosin filaments with accompanying myopathic changes. CONCLUSIONS: Deficiency of MYO18B is linked to a novel developmental disorder which combines KFA with myopathy. This suggests a widespread developmental role for this gene in humans, as observed for its murine ortholog.
Assuntos
Fácies , Síndrome de Klippel-Feil/diagnóstico , Síndrome de Klippel-Feil/genética , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Mutação , Miosinas/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Criança , Mapeamento Cromossômico , Consanguinidade , Análise Mutacional de DNA , Feminino , Homozigoto , Humanos , Masculino , Músculo Esquelético/patologia , Músculo Esquelético/ultraestrutura , Linhagem , Fenótipo , Coluna Vertebral/patologia , SíndromeRESUMO
Very-long-chain fatty acids (VLCFAs) play important roles in membrane structure and cellular signaling, and their contribution to human health is increasingly recognized. Fatty acid elongases catalyze the first and rate-limiting step in VLCFA synthesis. Heterozygous mutations in ELOVL4, the gene encoding one of the elongases, are known to cause macular degeneration in humans and retinal abnormalities in mice. However, biallelic ELOVL4 mutations have not been observed in humans, and murine models with homozygous mutations die within hours of birth as a result of a defective epidermal water barrier. Here, we report on two human individuals with recessive ELOVL4 mutations revealed by a combination of autozygome analysis and exome sequencing. These individuals exhibit clinical features of ichthyosis, seizures, mental retardation, and spasticity-a constellation that resembles Sjögren-Larsson syndrome (SLS) but presents a more severe neurologic phenotype. Our findings identify recessive mutations in ELOVL4 as the cause of a neuro-ichthyotic disease and emphasize the importance of VLCFA synthesis in brain and cutaneous development.
Assuntos
Anormalidades Múltiplas/genética , Proteínas do Olho/genética , Genes Recessivos , Ictiose/genética , Deficiência Intelectual/genética , Proteínas de Membrana/genética , Quadriplegia/genética , Anormalidades Múltiplas/diagnóstico , Sequência de Bases , Pré-Escolar , Consanguinidade , Deficiências do Desenvolvimento/genética , Exoma , Evolução Fatal , Ácidos Graxos/metabolismo , Estudos de Associação Genética , Humanos , Ictiose/diagnóstico , Deficiência Intelectual/diagnóstico , Masculino , Quadriplegia/diagnóstico , Análise de Sequência de DNARESUMO
BACKGROUND: Intellectual disability (ID) is one of the most common forms of disability worldwide, displaying a wide range of aetiologies and affecting nearly 2% of the global population. OBJECTIVE: To describe a novel autosomal recessive form of ID with strabismus and its underlying aetiology. MATERIALS AND METHODS: Autozygosity mapping, linkage analysis and exome sequencing were performed in a large multiplex consanguineous family that segregates ID and strabismus. Exome sequencing was independently performed in three other consanguineous families segregating the same disease. Direct sequencing of the resulting candidate gene was performed in four additional families with the same phenotype. RESULTS: A single missense mutation was identified in ADAT3 in all studied families on an ancient ancestral haplotype. This gene encodes one of two eukaryotic proteins that are necessary for the deamination of adenosine at position 34 to inosine in t-RNA. Our results show the first human mutation in the t-RNA editing machinery and expand the landscape of pathways involved in the pathogenesis of ID.
Assuntos
Adenosina Desaminase/genética , Deficiência Intelectual/genética , RNA de Transferência/genética , Estrabismo/genética , Sequência de Aminoácidos , Sequência de Bases , Estudos de Coortes , Consanguinidade , Exoma/genética , Feminino , Genes Recessivos , Ligação Genética , Haplótipos , Homozigoto , Humanos , Masculino , Dados de Sequência Molecular , Mutação , Linhagem , RNA de Transferência/metabolismoRESUMO
One of us recently described an apparently novel ocular syndrome characterized by microcornea, myopic chorioretinal atrophy, and telecanthus (MMCAT) in a number of Saudi families. Consistent with the presumed pseudodominant inheritance in one of the original families, we show that MMCAT maps to a single autozygous locus on chr16q23.1 in which exome sequencing revealed a homozygous missense change in ADAMTS18. Direct sequencing of this gene in four additional probands with the same phenotype revealed three additional homozygous changes in ADAMTS18 including two nonsense mutations. Reassuringly, the autozygomes of all probands overlap on the same chr16q23.1 locus, further supporting the positional mapping of MMCAT to ADAMTS18. ADAMTS18 encodes a member of a family of metalloproteinases that are known for their role in extracellular matrix remodeling, and previous work has shown a strong expression of Adamts18 in the developing eye. Our data suggest that ADAMTS18 plays an essential role in early eye development and that mutations therein cause a distinct eye phenotype that is mainly characterized by microcornea and myopia.
Assuntos
Proteínas ADAM/genética , Córnea/anormalidades , Distrofias Hereditárias da Córnea/genética , Anormalidades Craniofaciais/genética , Anormalidades do Olho/genética , Oftalmopatias Hereditárias/genética , Miopia Degenerativa/genética , Proteínas ADAMTS , Sequência de Aminoácidos , Criança , Cromossomos Humanos Par 6 , Códon sem Sentido , Córnea/patologia , Exoma , Anormalidades do Olho/fisiopatologia , Oftalmopatias Hereditárias/fisiopatologia , Humanos , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Linhagem , Fenótipo , Filogenia , Arábia Saudita , Análise de Sequência de DNARESUMO
Hereditary forms of cataract are genetically heterogeneous. Mutations in crystallin genes account for most Mendelian forms, but identification of other cataract genes has provided insights into additional molecular mechanisms that control lens transparency. In a multiplex consanguineous family with isolated congenital cataract, we identified a novel autosomal recessive cataract locus on 7q33-q36.1. Exome sequencing revealed a splice-site mutation in AGK, encoding acylglycerol kinase, which we confirm led to aberrant splicing and predicted premature truncation. This is the first mutation in this lipid metabolism gene to be implicated in the development of isolated cataract, although it remains to be seen if the mechanism involves perturbation of lenticular lipid composition or aberrant signaling during lens morphogenesis.
Assuntos
Catarata/genética , Genes Recessivos , Mutação , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Adolescente , Sequência de Bases , Criança , Cromossomos Humanos Par 7 , Consanguinidade , Éxons , Feminino , Genótipo , Humanos , Escore Lod , Masculino , Dados de Sequência Molecular , Linhagem , Sítios de Splice de RNARESUMO
BACKGROUND: Pediatric cataract is an important preventable blinding disease. Previous studies have estimated 10-25% of cases to be genetic in etiology. METHODS: In an effort to characterize the genetics of cataract in our population, we have conducted a comprehensive clinical and genomic analysis (including autozygome and exome analysis) on a series of 38 index patients. RESULTS: Pediatric cataract is genetic in at least 79% of the study families. Although crystallins accounted for most of the mutant alleles, mutations in other genes were encountered, including recessive mutations in genes that usually cause the disease in a dominant manner. In addition, several novel candidate genes (MFSD6L, AKR1E2, RNLS, and CYP51A1) were identified. CONCLUSION: Pediatric cataract is typically a genetic disease, usually autosomal recessive, in Saudi Arabia. Although defining a specific cataract phenotype can sometimes predict the genetic cause, genomic analysis is often required to unravel the causative mutation given the marked genetic heterogeneity. The identified novel candidate genes require independent confirmation in future studies.
Assuntos
Catarata/genética , Criança , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Exoma , Proteínas do Olho/genética , Feminino , Efeito Fundador , Estudos de Associação Genética , Genoma Humano , Homozigoto , Humanos , Proteínas de Filamentos Intermediários/genética , Masculino , Proteínas Associadas aos Microtúbulos , Monoaminoxidase/genética , Mutação de Sentido Incorreto , N-Acetilglucosaminiltransferases/genética , Receptor EphA2/genética , Arábia Saudita , Esterol 14-Desmetilase/genética , Fatores de Transcrição/genética , Cadeia B de beta-Cristalina/genéticaRESUMO
BACKGROUND: Knobloch syndrome (KS) is a developmental disorder characterised by occipital skull defect, high myopia, and vitreo-retinal degeneration. Although genetic heterogeneity has been suspected, COL18A1 is the only known KS disease gene to date. OBJECTIVE: To identify a novel genetic cause of KS in a cohort of Saudi KS patients enrolled in this study. METHODS: When COL18A1 mutation was excluded, autozygosity mapping was combined with exome sequencing. RESULTS: In one patient with first cousin parents, COL18A1 was excluded by both linkage and direct sequencing. By filtering variants generated on exome sequencing using runs of autozygosity in this simplex case, the study identified ADAMTS18 as the only gene carrying a homozygous protein altering mutation. It was also shown that Adamts18 is expressed in the lens and retina in the developing murine eye. CONCLUSION: The power of combining exome and autozygome analysis in the study of genetics of autosomal recessive disorders, even in simplex cases, has been demonstrated.
Assuntos
Proteínas ADAM/genética , Encefalocele/genética , Mutação , Descolamento Retiniano/congênito , Proteínas ADAM/metabolismo , Proteínas ADAMTS , Animais , Sequência de Bases , Consanguinidade , Embrião de Mamíferos/metabolismo , Encefalocele/metabolismo , Encefalocele/patologia , Exoma , Feminino , Heterogeneidade Genética , Humanos , Cristalino/metabolismo , Masculino , Camundongos , Dados de Sequência Molecular , Linhagem , Fenótipo , Retina/metabolismo , Degeneração Retiniana , Descolamento Retiniano/genética , Descolamento Retiniano/metabolismo , Descolamento Retiniano/patologiaRESUMO
Our knowledge of disease genes in neurological disorders is incomplete. With the aim of closing this gap, we performed whole-exome sequencing on 143 multiplex consanguineous families in whom known disease genes had been excluded by autozygosity mapping and candidate gene analysis. This prescreening step led to the identification of 69 recessive genes not previously associated with disease, of which 33 are here described (SPDL1, TUBA3E, INO80, NID1, TSEN15, DMBX1, CLHC1, C12orf4, WDR93, ST7, MATN4, SEC24D, PCDHB4, PTPN23, TAF6, TBCK, FAM177A1, KIAA1109, MTSS1L, XIRP1, KCTD3, CHAF1B, ARV1, ISCA2, PTRH2, GEMIN4, MYOCD, PDPR, DPH1, NUP107, TMEM92, EPB41L4A, and FAM120AOS). We also encountered instances in which the phenotype departed significantly from the established clinical presentation of a known disease gene. Overall, a likely causal mutation was identified in >73% of our cases. This study contributes to the global effort toward a full compendium of disease genes affecting brain function.
Assuntos
Doenças do Sistema Nervoso Central/genética , Estudos de Associação Genética , Doenças do Sistema Nervoso Central/patologia , Mapeamento Cromossômico , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Masculino , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNARESUMO
Corneal enlargement during the first 3 years of life can be a sign of early childhood glaucoma and optic nerve head cupping is a useful confirmatory finding. We report 3 children with corneal enlargement without optic nerve head cupping who had recessive CYP1B1 mutations, the most common identifiable cause of primary congenital glaucoma. One child later developed unilateral Haab striae, still in the absence of optic disk cupping. These cases illustrate that CYP1B1-related corneal changes can occur in young children without visible optic nerve head damage.
Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Doenças da Córnea/genética , Glaucoma/congênito , Mutação , Disco Óptico/patologia , Pré-Escolar , Citocromo P-450 CYP1B1 , Feminino , Genes Recessivos , Glaucoma/genética , Humanos , Lactente , MasculinoRESUMO
Iris anomalies associated with congenital or early-childhood glaucoma include stable primary developmental abnormalities such as those associated with the Axenfeld-Rieger spectrum and aniridia. Secondary generalized iris atrophy from uncontrolled intraocular pressure is another potential iris finding in pediatric glaucoma. We document an unusual pattern of acquired peripheral circumferential iris degeneration in 2 unrelated children with otherwise-controlled congenital glaucoma. Genetic testing revealed a common homozygous CYP1B1 mutation in one (p.Gly61Glu) and a novel heterozygous FOXC1 deletion in the other (p.Tyr81_Pro95del).
Assuntos
Anormalidades do Olho/complicações , Hidroftalmia/etiologia , Iris/anormalidades , Anti-Hipertensivos/uso terapêutico , Hidrocarboneto de Aril Hidroxilases/genética , Citocromo P-450 CYP1B1 , Quimioterapia Combinada , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Feminino , Fatores de Transcrição Forkhead/genética , Humanos , Hidroftalmia/diagnóstico , Hidroftalmia/tratamento farmacológico , Lactente , Pressão Intraocular/efeitos dos fármacos , Mutação Puntual , Deleção de Sequência , Sulfonamidas/uso terapêutico , Tiofenos/uso terapêutico , Timolol/uso terapêuticoRESUMO
Nonsyndromic primary newborn glaucoma, the most severe form of primary congenital glaucoma, typically is bilateral and often the result of CYP1B1 mutations, particularly in certain consanguineous populations. Truly unilateral cases are uncommon and genetically not well studied. During a 9-year period, we tested 5 consecutive children with unilateral primary newborn glaucoma from Saudi Arabia, where CYP1B1 mutations are the cause for 91% of bilateral primary newborn glaucoma cases. None of these children with unilateral primary newborn glaucoma harbored CYP1B1 mutations, suggesting that in this population the pathogenesis of unilateral disease differs from that of bilateral disease.
Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Hidroftalmia/genética , Criança , Pré-Escolar , Consanguinidade , Citocromo P-450 CYP1B1 , Análise Mutacional de DNA , Feminino , Humanos , Hidroftalmia/diagnóstico , Hidroftalmia/etnologia , Pressão Intraocular , Masculino , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Arábia Saudita/epidemiologia , Tonometria OcularRESUMO
PURPOSE: To correlate clinical examination with underlying genotype in asymptomatic females who are potential carriers of X-linked developmental cataract (Nance-Horan syndrome). METHODS: An ophthalmologist blind to the pedigree performed comprehensive ophthalmic examination for 16 available family members (two affected and six asymptomatic females, five affected and three asymptomatic males). Facial features were also noted. Venous blood was collected for sequencing of the gene NHS. RESULTS: All seven affected family members had congenital or infantile cataract and facial dysmorphism (long face, bulbous nose, abnormal dentition). The six asymptomatic females ranged in age from 4-35 years old. Four had posterior Y-suture centered lens opacities; these four also exhibited the facial dysmorphism of the seven affected family members. The fifth asymptomatic girl had scattered fine punctate lens opacities (not centered on the Y-suture) while the sixth had clear lenses, and neither exhibited the facial dysmorphism. A novel NHS mutation (p.Lys744AsnfsX15 [c.2232delG]) was found in the seven patients with congenital or infantile cataract. This mutation was also present in the four asymptomatic girls with Y-centered lens opacities but not in the other two asymptomatic girls or in the three asymptomatic males (who had clear lenses). CONCLUSIONS: Lens opacities centered around the posterior Y-suture in the context of certain facial features were sensitive and specific clinical signs of carrier status for NHS mutation in asymptomatic females. Lens opacities that did not have this characteristic morphology in a suspected female carrier were not a carrier sign, even in the context of her affected family members.
Assuntos
Catarata/congênito , Doenças Genéticas Ligadas ao Cromossomo X/genética , Genótipo , Mutação , Proteínas Nucleares/genética , Anormalidades Dentárias/genética , Adolescente , Adulto , Idoso , Catarata/diagnóstico , Catarata/genética , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Humanos , Cristalino/patologia , Masculino , Proteínas de Membrana , Linhagem , Fenótipo , Reação em Cadeia da Polimerase , Anormalidades Dentárias/diagnóstico , Acuidade Visual/fisiologiaRESUMO
AIM: To clinically and genetically characterise central pulverulent cataract in a consecutive cohort of children from the Arabian Peninsula who were referred for ophthalmic evaluation. METHODS: Ophthalmic examination, homozygosity mapping in a consanguineous family and candidate gene analysis. RESULTS: All 16 children (4-16 years old, mean 9 years; seven girls and nine boys from 10 families) had bilateral central nuclear dust-like lenticular opacities. Two patients (one family) had cortical riders and six had associated strabismus. Cycloplegic retinoscopy was usually hyperopic (13/16; right eye spherical equivalent +0.50 to +6.25 dioptres, mean +3.50) but was sometimes myopic (3/16; right eye spherical equivalent -0.50 to -11.75, mean -6.50). In children with amblyopia (5/16), the cause was significant uncorrected ametropias rather than the lens opacities. Three patients had uncomplicated unilateral cataract surgery suggested by an outside second opinion that did not improve best-corrected visual acuity. Homozygosity mapping for one consanguineous family suggested the candidate gene CRYBB1. Sequencing of this gene revealed a homozygous c.171del mutation (p.N58Tfs*107) with a shared haplotype in all 16 children. In asymptomatic carrier parents from five of the six families available for careful slit-lamp examination, occasional central dot lenticular opacities were documented. CONCLUSIONS: Central pulverulent cataract in this consanguineous population does not significantly impact visual acuity during early childhood, can be associated with significant ametropias (with amblyopia and/or strabismus) and is specific for a homozygous CRYBB1 founder mutation. Primary management in children is typically spectacle correction based on cycloplegic retinoscopy to treat significant refractive error rather than paediatric cataract surgery.
Assuntos
Catarata/genética , Consanguinidade , Mutação da Fase de Leitura/genética , Cadeia B de beta-Cristalina/genética , Adolescente , Ambliopia/genética , Catarata/patologia , Catarata/terapia , Criança , Pré-Escolar , Óculos , Feminino , Homozigoto , Humanos , Masculino , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Retinoscopia , Arábia Saudita , Estrabismo/genética , Acuidade Visual/fisiologiaRESUMO
BACKGROUND: Knobloch syndrome is defined as a triad of occipital defect, high myopia and vitreo-retinal degeneration (often with later retinal detachment); however, the ocular phenotype is not well defined. This report characterises eye findings of the syndrome in children with genetically confirmed disease. METHODS: Case series of Saudi children with previously documented homozygous mutations in COL18A1 or ADAMTS18. RESULTS: All eight children (4-15 years old; five families) had smooth (cryptless) irides, high myopia (-10 to -20 dioptres) and distinctive vitreo-retinal degeneration consisting of diffuse very severe retinal pigment epithelium atrophic changes with prominent choroidal vessel show, macular atrophic lesions with or without a 'punched out' appearance and white fibrillar vitreous condensations. In two probands and a sibling, this distinctive retinal appearance was the basis for initial clinical diagnosis. Six children had temporal ectopia lentis and four had posterior perinuclear lens opacity. Additional features included developmental delay (two), epilepsy (one) and heterotopic grey matter in the lateral ventricles (one). Four children had no clinically discernible occipital defect. CONCLUSION: Taken together, smooth iridies, ectopia lentis and characteristic vitreo-retinal degeneration seem pathognomonic. Although it is a defining feature of the syndrome, clinically discernible occipital defect is not a sine qua non for the diagnosis. Ophthalmologists are uniquely able to diagnose Knobloch syndrome.