RESUMO
BACKGROUND: Variations in ZNF469 have been associated with Brittle Cornea Syndrome that presents with bluish sclera, loss of vision after trivial trauma, arachnodactyly, and joint laxity. MATERIALS AND METHODS: Detailed medical and family history, physical examination, and molecular analysis. RESULTS: A 21-year-old female presented with bluish discoloration of sclera, diminution of vision following trivial trauma in childhood along with hearing loss and systemic features of arachnodactyly and joint laxity. Clinical diagnosis of brittle cornea syndrome was made which was molecularly proven using next-generation sequencing which identified compound heterozygosity in ZNF469 for pathogenic and likely pathogenic nonsense variants. One variant namely NM_001367624.2:c.5882dup was identified in the exon 3 which was novel and classified as likely pathogenic according to American College of Medical Genetics (ACMG) criteria for variant classification. Another variant NM_001367624.2:c.8992C>T in the exon 2 was classified as pathogenic for Brittle Cornea Syndrome 1. CONCLUSIONS: The report adds to the allelic heterogeneity in ZNF469 causative of Brittle Cornea Syndrome 1 and shall acquaint the physicians about this potentially vision threatening, underdiagnosed, rare syndrome.
Assuntos
Alelos , Instabilidade Articular , Fatores de Transcrição , Humanos , Feminino , Adulto Jovem , Fatores de Transcrição/genética , Instabilidade Articular/genética , Instabilidade Articular/diagnóstico , Instabilidade Articular/congênito , Índia , Anormalidades da Pele/genética , Anormalidades da Pele/diagnóstico , Aracnodactilia/genética , Aracnodactilia/diagnóstico , Doenças do Tecido Conjuntivo/genética , Doenças do Tecido Conjuntivo/diagnóstico , Anormalidades do Olho/genética , Anormalidades do Olho/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala , Linhagem , Mutação , Éxons/genética , Anormalidades Múltiplas/genética , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/diagnóstico , Dermatopatias Genéticas/genética , Dermatopatias Genéticas/diagnóstico , Dermatopatias Genéticas/patologiaRESUMO
Background: Neurofibromatosis type 1 (NF1) is a unique, highly penetrant neuro-cutaneous disorder with a wide range of manifestations. Though the clinical diagnosis of NF1 is straight forward, there can be other disorders which mimic NF1, especially its cutaneous features. Here we describe the clinical and mutation spectrum of a series of individuals whose primary diagnosis was NF1 or NF1 related disorders. Methods: We have screened 29 unrelated individuals who fulfilled the clinical criteria of NF1. Whole exome sequencing (WES) was done in all individuals except one with suspected microdeletion syndrome with NF1 in whom Cytogenetic microarray (CMA) was done. Results: Out of 29 suspected patients, 25 had germline pathogenic/likely pathogenic variants involving NF1 gene. Five novel and 20 known variants in coding and non-coding regions were identified, among them 7 variants were deletions (28%), 7 nonsense (28%), 3 splice-site (12%), 4 missense (16%), 2 duplications (8%) and 2 (8%) were contiguous deletions. In those where NF1 variants were not detected, 3 had neurofibromatosis type 2 (NF2) and 1 rare autosomal recessive form of Elher Danlos syndrome. Conclusion: We hereby present the wide range of manifestations in different age groups and the mutation spectrum ranging from small scale variants to contiguous gene deletion syndromes involving NF1 gene. We highlight the usefulness of molecular testing and its importance in tumor surveillance and genetic counseling in this disorder.