A novel SIX3 mutation segregates with holoprosencephaly in a large family.
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.
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Benjamin D
BD
Solomon
Felicitas
F
Lacbawan
Mahim
M
Jain
Sabina
S
Domené
Erich
E
Roessler
Cynthia
C
Moore
William B
WB
Dobyns
Maximilian
M
Muenke
D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D020090:Chromosome Segregation; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D016142:Holoprosencephaly / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D055815:Young Adult; D000097607:Homeobox Protein SIX3
D005136:Eye Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D000097607:Homeobox Protein SIX3