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. 2009 May;149A(5):919-25.
doi: 10.1002/ajmg.a.32813.

A novel SIX3 mutation segregates with holoprosencephaly in a large family

Benjamin D Solomon  1 , Felicitas Lacbawan, Mahim Jain, Sabina Domené, Erich Roessler, Cynthia Moore, William B Dobyns, Maximilian Muenke
Affiliations

A novel SIX3 mutation segregates with holoprosencephaly in a large family

Benjamin D Solomon et al. Am J Med Genet A. 2009 May.

Abstract

Holoprosencephaly is the most common structural malformation of the forebrain in humans and has a complex etiology including chromosomal aberrations, single gene mutations and environmental components. Here we present the pertinent clinical findings among members of an unusually large kindred ascertained over 15 years ago following the evaluation and subsequent genetic work-up of a female infant with congenital anomalies. A genome-wide scan and linkage analysis showed only suggestive evidence of linkage to markers on chromosome 2 among the most likely of several pedigree interpretations. We now report that a novel missense mutation in the SIX3 holoprosencephaly gene is the likely cause in this family. Molecular genetic analysis and/or clinical characterization now show that at least 15 members of this family are presumed SIX3 mutation gene carriers, with clinical manifestations ranging from phenotypically normal adults (non-penetrance) to alobar holoprosencephaly incompatible with postnatal life. This particular family represents a seminal example of the variable manifestations of gene mutations in holoprosencephaly and difficulties encountered in their elucidation.

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Figures

Figure 1
Figure 1
Pedigree of family.
Figure 2
Figure 2
a: Proposita (IV.19) with macrocephaly, hypotelorism, hypoplastic philtrum, and low-set ears; (b,c) head CT showing alobar HPE and hydrocephalus; (d) mother (III.7); (e) aunt (III.8); (f) grandmother (II.2); (g) great-uncle (II.5). All individuals had evidence for the presence of the SIX3 mutation. The proposita’s relatives show various signs of microform HPE, with varying degrees of microcephaly, hypotelorism, and thin nasal bridges.
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References

    1. Abecasis GR, Cardon LR, Cookson WO, Sham PC, Cherny SS. Association analysis in a variance components framework. Genet Epidemiol. 2001;21:S341–S346. - PubMed
    1. Barkovich AJ, Quint DJ. Middle interhemispheric fusion: Anunusual variant of holoprosencephaly. Am J Neuroradiol. 1993;14:431–440. - PMC - PubMed
    1. Bendavid C, Dubourg C, Gicquel I, Pasquier L, Saugier-Veber P, Durou MR, Jaillard S, Frebourg T, Haddad BR, Henry C, Odent S, David V. Molecular evaluation of foetuses with holoprosencephaly shows high incidence of microdeletions in the HPE genes. Hum Genet. 2006a;119:1–8. - PubMed
    1. Bendavid C, Haddad BR, Griffin A, Huizing M, Dubourg C, Gicquel I, Cavalli LR, Pasquier L, Shanske AL, Long R, Ouspenskaia M, Odent S, Lacbawan F, David V, Muenke M. Multicolour FISH and quantitative PCR can detect submicroscopic deletions in holoprosencephaly patients with a normal karyotype. J Med Genet. 2006b;43:496–500. - PMC - PubMed
    1. Brown SA, Warburton D, Brown LY, Yu CY, Roeder ER, Stengel-Rutkowski S, Hennekam RC, Muenke M. Holoprosencephaly due to mutations in ZIC2, a homologue of Drosophila odd-paired. Nat Genet. 1998;20:180–183. - PubMed

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