SIX3 deletions and incomplete penetrance in families affected by holoprosencephaly

Six3 dosage mediates the pathogenesis of holoprosencephaly.

Holoprosencephaly (HPE) is defined as the incomplete separation of the two cerebral hemispheres. The pathology of HPE is variable and, based on the severity of the defect, HPE is divided into alobar, semilobar, and lobar. Using a novel hypomorphic Six3 allele, we demonstrate in mice that variability in Six3 dosage results in different HPE phenotypes. Furthermore, we show that whereas the semilo...

Holoprosencephaly in deletions of proximal chromosome 14q.

Incomplete penetrance of MHC

We propose an approach to understanding incomplete penetrance of disease susceptibility genes as a method of studying the underlying mechanisms of polygenic diseases. Incomplete penetrance is the failure of genetically susceptible individuals to exhibit a trait. We define as baseline penetrance that which occurs in genetically identical (monozygotic) twins of an index subject with a major histo...

Clinical spectrum of SIX3-associated mutations in holoprosencephaly: correlation between genotype, phenotype and function.

BACKGROUND Holoprosencephaly (HPE) is the most common structural malformation of the human forebrain. There are several important HPE mutational target genes, including the transcription factor SIX3, which encodes an early regulator of Shh, Wnt, Bmp and Nodal signalling expressed in the developing forebrain and eyes of all vertebrates. OBJECTIVE To characterise genetic and clinical findings i...

First occurrence of aprosencephaly/atelencephaly and holoprosencephaly in a family with a SIX3 gene mutation and phenotype/genotype correlation in our series of SIX3 mutations.

A prosencephaly/atelencephaly (AP/AT) refers to rudimentary prosencephalon, while holoprosencephaly (HPE) is a failure of telencephalon cleavage. The question of whether AP/AT results from a disruptive lesion or a growth failure is still debated. 2 At least six causal genes, namely SHH, ZIC2, SIX3, TGIF, PATCHED, and CRIPTO (TDGF1), are linked to HPE and to ventral and dorsal patterning defect ...