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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

Aprosencephaly/atelencephaly (AP/AT) refers to rudimentary prosencephalon, while holoprosencephaly (HPE) is a failure of telencephalon cleavage.1 The question of whether AP/AT results from a disruptive lesion or a growth failure is still debated.1,2 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 of the neural tube.3–7

We report the first occurrence of AP/AT and HPE in a non-consanguineous family with three affected sibs, carrying a maternally inherited mutation of the SIX3 gene. A phenotype/genotype correlation in the series of seven SIX3 mutations found in our cohort of 210 HPE probands is provided.

Systematic sequencing of the entire coding region of the SHH , ZIC2 , TGIF , and SIX3 genes has been performed in a series of 210 non-chromosomal HPE probands including 56 patients reported previously.8 Probands were included in the study after brain imaging, karyotyping, and detailed clinicopathological studies, referring to the protocol for fetuses.9 Mutational analyses were performed as detailed elsewhere.10

Of the 210 patients screened, seven had mutations in the SIX3 gene but none in other HPE causing genes. The findings are illustrated in figs 1, 2, and 3. HPE was associated with AP/AT in three affected sibs carrying a maternally inherited mutation of SIX3 .



 Figure 1 SIX3 mutations in HPE: representative pedigrees showing probands and relatives. Filled symbols indicate alobar HPE with synophthalmy or cyclopy. Three quarters filled symbols indicate alobar or semi-lobar HPE without synophthalmy. Half filled symbols indicate minor features of the HPE spectrum with hypotelorism, single upper incisor, and mental retardation. Quarter filled symbols indicate isolated hypotelorism. M, SIX3 mutation carrier; N, no mutation. (A) Familial case with missense mutation in the SIX domain leading …