Open AccessNew <b><i>SHH</i></b> and Known <b><i>SIX3</i></b> Variants in a Series of Latin American Patients with Holoprosencephaly
Author(s) -
Viviane Freitas de Castro,
Daniel Mattos,
Flávia Carvalho,
Denise Pontes Cavalcanti,
Milagros DueñasRoque,
Juan Clinton Llerena,
Viviana Cosentino,
Rachel Sayuri Honjo,
Júlio César Loguercio Leite,
Maria Teresa Vieira Sanseverino,
Márcia Pereira Alves de Souza,
Pricila Bernardi,
Ana Maria Bolognese,
Luiz Carlos Santana da Silva,
Pablo Barbero,
Patrícia Correia,
Larissa Souza Mario Bueno,
Clarice Pagani Savastano,
Iêda M. Orioli
Publication year - 2021
Publication title -
molecular syndromology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.609
H-Index - 36
eISSN - 1661-8777
pISSN - 1661-8769
DOI - 10.1159/000515044
Subject(s) - genetics , holoprosencephaly , penetrance , phenotype , gene , biology , pregnancy , fetus
Holoprosencephaly (HPE) is the failure of the embryonic forebrain to develop into 2 hemispheres promoting midline cerebral and facial defects. The wide phenotypic variability and causal heterogeneity make genetic counseling difficult. Heterozygous variants with incomplete penetrance and variable expressivity in the SHH , SIX3 , ZIC2 , and TGIF1 genes explain ∼25% of the known causes of nonchromosomal HPE. We studied these 4 genes and clinically described 27 Latin American families presenting with nonchromosomal HPE. Three new SHH variants and a third known SIX3 likely pathogenic variant found by Sanger sequencing explained 15% of our cases. Genotype-phenotype correlation in these 4 families and published families with identical or similar driver gene, mutated domain, conservation of residue in other species, and the type of variant explain the pathogenicity but not the phenotypic variability. Nine patients, including 2 with SHH pathogenic variants, presented benign variants of the SHH , SIX3 , ZIC2 , and TGIF1 genes with potential alteration of splicing, a causal proposition in need of further studies. Finding more families with the same SIX3 variant may allow further identification of genetic or environmental modifiers explaining its variable phenotypic expression.