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
- 1Unité de Génétique Médicale, Hôpital SUD, Rennes, France
- 2Laboratoire de Génétique Moléculaire, Hôpital Pontchaillou, Rennes, France
- 3Laboratoire de Foetopathologie, CHU Saint-Antoine, Paris, France
- 4Service d’Histo-Embryologie et Cytogénétique, Hôpital Necker, Paris, France
- Correspondence to: Dr S Odent Unité de Génétique Médicale, Hôpital SUD, 16 Bd de Bulgarie BP 90347, 35203 Rennes cedex 2, France;
- Received 27 August 2004
- Accepted 1 September 2004
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
RESULTS AND DISCUSSION
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.