RESUMO
Trichorhinophalangeal syndrome type I (TRPSI) is a rare disorder that causes distinctive ectodermal, facial, and skeletal features affecting the hair (tricho-), nose (rhino-), and fingers and toes (phalangeal) and is inherited in an autosomal dominant pattern. TRPSI is caused by loss of function variants in TRPS1, involved in the regulation of chondrocyte and perichondrium development. Pathogenic variants in TRPS1 include missense mutations and deletions with variable breakpoints, with only a single instance of an intragenic duplication reported to date. Here we report an affected individual presenting with a classic TRPSI phenotype who is heterozygous for a de novo intragenic â¼36.3-kbp duplication affecting exons 2-4 of TRPS1 Molecular analysis revealed the duplication to be in direct tandem orientation affecting the splicing of TRPS1 The aberrant transcripts are predicted to produce a truncated TRPS1 missing the nuclear localization signal and the GATA and IKAROS-like zinc-finger domains resulting in functional TRPS1 haploinsufficiency. Our study identifies a novel intragenic tandem duplication of TRPS1 and highlights the importance of molecular characterization of intragenic duplications.
Assuntos
Dedos/anormalidades , Doenças do Cabelo/genética , Síndrome de Langer-Giedion/genética , Nariz/anormalidades , Proteínas Repressoras/genética , Idoso , Criança , Proteínas de Ligação a DNA/genética , Éxons/genética , Família , Feminino , Duplicação Gênica/genética , Doenças do Cabelo/etiologia , Humanos , Síndrome de Langer-Giedion/etiologia , Masculino , Pessoa de Meia-Idade , Mutação , Mutação de Sentido Incorreto/genética , Linhagem , Fenótipo , Splicing de RNA/genética , Proteínas Repressoras/metabolismo , Deleção de Sequência/genética , Fatores de Transcrição/genética , Dedos de Zinco/genéticaRESUMO
We describe two unrelated patients, a 12-yr-old female and a 6-yr-old male, with congenital contractures and severe congenital muscular atrophy. Exome and genome sequencing of the probands and their unaffected parents revealed that they have the same de novo deletion in BICD2 (c.1636_1638delAAT). The variant, which has never been reported, results in an in-frame 3-bp deletion and is predicted to cause loss of an evolutionarily conserved asparagine residue at position 546 in the protein. Missense mutations in BICD2 cause autosomal dominant spinal muscular atrophy, lower-extremity predominant 2 (SMALED2), a disease characterized by muscle weakness and arthrogryposis of early onset and slow progression. The p.Asn546del clusters with four pathogenic missense variants in a region that likely binds molecular motor KIF5A. Protein modeling suggests that removing the highly conserved asparagine residue alters BICD2 protein structure. Our findings support a broader phenotypic spectrum of BICD2 mutations that may include severe manifestations such as cerebral atrophy, seizures, dysmorphic facial features, and profound muscular atrophy.