Novel mutations in the TBX5 gene in patients with Holt-Oram Syndrome

The Holt-Oram syndrome (HOS) is an autosomal dominant condition characterized by upper limb and cardiac malformations. Mutations in the TBX5 gene cause HOS and have also been associated with isolated heart and arm defects. Interactions between the TBX5, GATA4 and NKX2.5 proteins have been reported in humans. We screened the TBX5, GATA4, and NKX2.5 genes for mutations, by direct sequencing, in 32 unrelated patients presenting classical (8) or atypical HOS (1), isolated congenital heart defects (16) or isolated upper-limb malformations (7). Pathogenic mutations in the TBX5 gene were found in four HOS patients, including two new mutations (c.374delG; c.678G > T) in typical patients, and the hotspot mutation c.835C > T in two patients, one of them with an atypical HOS phenotype involving lower-limb malformations. Two new mutations in the GATA4 gene were found in association with isolated upper-limb malformations, but their clinical significance remains to be established. A previously described possibly pathogenic mutation in the NKX2.5 gene (c.73C > 7) was detected in a patient with isolated heart malformations and also in his clinically normal father.

Array-CGH testing in spontaneous abortions with normal karyotypes

In about 50 percent of first trimester spontaneous abortion the cause remains undetermined after standard cytogenetic investigation. We evaluated the usefulness of array-CGH in diagnosing chromosome abnormalities in products of conception from first trimester spontaneous abortions. Cell culture was carried out in short- and long-term cultures of 54 specimens and cytogenetic analysis was successful in 49 of them. Cytogenetic abnormalities (numerical and structural) were detected in 22 (44.89 percent) specimens. Subsequent, array-CGH based on large insert clones spaced at ~1 Mb intervals over the whole genome was used in 17 cases with normal G-banding karyotype. This revealed chromosome aneuplodies in three additional cases, giving a final total of 51 percent cases in which an abnormal karyotype was detected. In keeping with other recently published works, this study shows that array-CGH detects abnormalities in a further ~10 percent of spontaneous abortion specimens considered to be normal using standard cytogenetic methods. As such, array-CGH technique may present a suitable complementary test to cytogenetic analysis in cases with a normal karyotype.

Polidactilia pós-axial e miopia progressiva / Postaxial polydactyly and progressive myopia

O presente trabalho apresenta três casos de associaçäo de miopia progressiva com polidactilia pós-axial, sendo que dois säo irmäos do sexo masculino, filhos de casal näo consanguíneo e o terceiro caso é de uma menina filha de pais consanguíneos. Verificou-se na literatura apenas um relato, de Czeizel e Brooser, em 1986, em que é descrita a mesma associaçäo de defeitos, transmitindo-se em quatro geraçöes de forma autossômica dominante. Acreditamos que nossos pacientes apresentam a mesma síndrome, porém nestas duas famílias existem indícios de que a transmissäo ocorra de forma autossômica recessiva.

Holoprosencephaly as a result of an unbalanced familial translocation rcp(7;18) (q36;q21)

Apresenta-se o caso de um recém-nascido do sexo masculino com uma síndrome malformativa caracterizada por agenesia da pré-maxila, holoprosencefalia alobar e outras malformaçöes congênitas. O estudo cromossômico revelou que a criança era portadora de uma duplicaçäo 18q e de uma deficiência 7q originárias de uma translocaçäo materna (7;18) (q36;q21). Este caso e outros relatados na literatura permitem estabelecer uma associaçäo preferencial entre o defeito de campo da holoprosencefalia e a monossomia 7q terminal