Molecular analysis of holoprosencephaly in South America.
Holoprosencephaly (HPE) is a spectrum of brain and facial malformations primarily reflecting genetic factors, such as chromosomal abnormalities and gene mutations. Here, we present a clinical and molecular analysis of 195 probands with HPE or microforms; approximately 72% of the patients were derived from the Latin American Collaborative Study of Congenital Malformations (ECLAMC), and 82% of the patients were newborns. Alobar HPE was the predominant brain defect in almost all facial defect categories, except for patients without oral cleft and median or lateral oral clefts. Ethmocephaly, cebocephaly, and premaxillary agenesis were primarily observed among female patients. Premaxillary agenesis occurred in six of the nine diabetic mothers. Recurrence of HPE or microform was approximately 19%. The frequency of microdeletions, detected using Multiplex Ligation-dependant Probe Amplification (MLPA) was 17% in patients with a normal karyotype. Cytogenetics or QF-PCR analyses revealed chromosomal anomalies in 27% of the probands. Mutational analyses in genes SHH, ZIC2, SIX3 and TGIF were performed in 119 patients, revealing eight mutations in SHH, two mutations in SIX3 and two mutations in ZIC2. Thus, a detailed clinical description of new HPE cases with identified genetic anomalies might establish genotypic and phenotypic correlations and contribute to the development of additional strategies for the analysis of new cases.
Estudo Colaborativo Latino Americano de Malformações Congênitas, Departamento de Genética, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil . ; Instituto Nacional de Genética Médica Populacional, Rio de Janeiro, RJ, Brazil .
Clarice Pagani
CP
Savastano
Departamento de Genética e Biologia Molecular, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil .
Kênia Balbi
KB
El-Jaick
Departamento de Genética, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil .
Marcelo Aguiar
MA
Costa-Lima
Maternidade Cândida Vargas, Instituto Cândida Vargas, João Pessoa, PB, Brazil .
Cristina Maria Batista
CM
Abath
Centro di Consulenza Genetica e di Teratologia della Riproduzione, Dipartimento Materno Infantile, ARNAS Garibaldi Nesima, Catania, CT, Italy .
Sebastiano
S
Bianca
Departamento de Genética Médica, Universidade Estadual de Campinas, Campinas, SP, Brazil .
Denise Pontes
DP
Cavalcanti
Serviço de Genética Médica, Hospital das Clínicas de Porto Alegre, Porto Alegre, RS, Brazil .
Têmis Maria
TM
Félix
Registro Campano Difetti Congeniti, Azienda Ospedaliera "Gaetano Rummo", Benevento, BN, Italy .
Gioacchino
G
Scarano
Centro de Genética Médica, Instituto Fernandes Figueira, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil .
Juan Clinton
JC
Llerena
Departamento de Genética e Biologia Molecular, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil . ; Estudo Colaborativo Latino Americano de Malformações Congênitas, Laboratório de Epidemiologia de Defeitos Congênitos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil .
Fernando Regla
FR
Vargas
Programa de Genética, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil .
Miguel Ângelo Martins
MÂ
Moreira
Programa de Genética, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil .
Hector N
HN
Seuánez
Instituto Nacional de Genética Médica Populacional, Rio de Janeiro, RJ, Brazil . ; Estudio Colaborativo Latino Americano de Malformaciones Congenitas, Centro de Educación Médica e Investigación Clínica, Buenos Aires, Argentina .
Eduardo Enrique
EE
Castilla
Estudo Colaborativo Latino Americano de Malformações Congênitas, Departamento de Genética, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil . ; Instituto Nacional de Genética Médica Populacional, Rio de Janeiro, RJ, Brazil .
Iêda Maria
IM
Orioli
ECLAMC; SHH; SIX3; ZIC2; holoprosencephaly