RESUMO
Catel-Manzke syndrome is characterized by Pierre Robin sequence and a unique form of bilateral hyperphalangy causing a clinodactyly of the index finger. We describe the identification of homozygous and compound heterozygous mutations in TGDS in seven unrelated individuals with typical Catel-Manzke syndrome by exome sequencing. Six different TGDS mutations were detected: c.892A>G (p.Asn298Asp), c.270_271del (p.Lys91Asnfs(∗)22), c.298G>T (p.Ala100Ser), c.294T>G (p.Phe98Leu), c.269A>G (p.Glu90Gly), and c.700T>C (p.Tyr234His), all predicted to be disease causing. By using haplotype reconstruction we showed that the mutation c.298G>T is probably a founder mutation. Due to the spectrum of the amino acid changes, we suggest that loss of function in TGDS is the underlying mechanism of Catel-Manzke syndrome. TGDS (dTDP-D-glucose 4,6-dehydrogenase) is a conserved protein belonging to the SDR family and probably plays a role in nucleotide sugar metabolism.
Assuntos
Deformidades Congênitas da Mão/genética , Oxirredutases/genética , Síndrome de Pierre Robin/genética , Adolescente , Adulto , Sequência de Aminoácidos , Pré-Escolar , Exoma/genética , Feminino , Deformidades Congênitas da Mão/enzimologia , Haplótipos , Heterozigoto , Homozigoto , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Dados de Sequência Molecular , Mutação , Oxirredutases/metabolismo , Linhagem , Síndrome de Pierre Robin/enzimologia , Alinhamento de Sequência , Análise de Sequência de DNA , Adulto JovemRESUMO
We report two new female patients with typical features of Catel-Manzke syndrome (MIM 302380) and the follow-up of the first patient affected by this syndrome. In addition to the Pierre Robin anomaly, the hallmark of this palatodigital syndrome is a bilateral hyperphalangy and clinodactyly of the index finger. Classified into four groups there are now (1) 23 reported cases of the typical, (2) six cases of the extended Catel-Manzke syndrome showing more than two accessory bones in the hand, (3) two patients showing unilateral hyperphalangy and clinodactyly of the index finger (4) two patients described with isolated features of the "Manzke dysostosis" without Pierre Robin anomaly. The karyotype of our three patients was normal. A search for submicroscopic chromosomal abnormalities by array CGH was performed. In addition, we sequenced candidate genes which are known to be involved in phalangeal development. However, no pathogenic aberrations or mutations were found.