OBJECTIVE: holoprosencephaly is the most common forebrain malformation syndrome with a multifactorial etiology. Currently, mutations are identified in 5-10% of non syndromic, non-chromosomal cases in at least 12 genes. We report the molecular prenatal diagnosis of a fetus with alobar holoprosencephaly. METHODS: CTG band karyotyping and array CGH genome-wide cytogenetic screenings were done, in conjunction with DNA sequence analyses of the SHH, ZIC2, SIX3 and TGIF genes in search of a molecular etiology and with comparison of findings to prior cases. RESULTS: standard CTG band karyotyping and array CGH genome-wide screening failed to identify plausible chromosome imbalances or structural anomalies. However, extensive sequencing of the genomic DNA from the fetus and both parents on all exon and exon-intron boundaries of the four most commonly mutated genes: SHH, ZIC2, SIX3 and TGIF, identified codon 100 of the sonic hedgehog (SHH) gene having a hotspot for loss-of-function mutations in our case and others. CONCLUSION: mutations in codon 100 of SHH were discovered in both sporadic and autosomal dominant inherited cases with evidence of variable expressivity and penetrance. Collectively, this study reinforces the complexity of genotype-phenotype correlations in the prenatal diagnosis of holoprosencephalic fetuses.
OBJECTIVE:holoprosencephaly is the most common forebrain malformation syndrome with a multifactorial etiology. Currently, mutations are identified in 5-10% of non syndromic, non-chromosomal cases in at least 12 genes. We report the molecular prenatal diagnosis of a fetus with alobar holoprosencephaly. METHODS: CTG band karyotyping and array CGH genome-wide cytogenetic screenings were done, in conjunction with DNA sequence analyses of the SHH, ZIC2, SIX3 and TGIF genes in search of a molecular etiology and with comparison of findings to prior cases. RESULTS: standard CTG band karyotyping and array CGH genome-wide screening failed to identify plausible chromosome imbalances or structural anomalies. However, extensive sequencing of the genomic DNA from the fetus and both parents on all exon and exon-intron boundaries of the four most commonly mutated genes: SHH, ZIC2, SIX3 and TGIF, identified codon 100 of the sonic hedgehog (SHH) gene having a hotspot for loss-of-function mutations in our case and others. CONCLUSION: mutations in codon 100 of SHH were discovered in both sporadic and autosomal dominant inherited cases with evidence of variable expressivity and penetrance. Collectively, this study reinforces the complexity of genotype-phenotype correlations in the prenatal diagnosis of holoprosencephalic fetuses.
Authors: Aimée D C Paulussen; Constance T Schrander-Stumpel; Demis C J Tserpelis; Matteus K M Spee; Alexander P A Stegmann; Grazia M Mancini; Alice S Brooks; Margriet Collée; Anneke Maat-Kievit; Marleen E H Simon; Yolande van Bever; Irene Stolte-Dijkstra; Wilhelmina S Kerstjens-Frederikse; Johanna C Herkert; Anthonie J van Essen; Klaske D Lichtenbelt; Arie van Haeringen; Mei L Kwee; Augusta M A Lachmeijer; Gita M B Tan-Sindhunata; Merel C van Maarle; Yvonne H J M Arens; Eric E J G L Smeets; Christine E de Die-Smulders; John J M Engelen; Hubertus J Smeets; Jos Herbergs Journal: Eur J Hum Genet Date: 2010-06-09 Impact factor: 4.246
Authors: S Odent; T Atti-Bitach; M Blayau; M Mathieu; J Aug; A L Delezo de; J Y Gall; B Le Marec; A Munnich; V David; M Vekemans Journal: Hum Mol Genet Date: 1999-09 Impact factor: 6.150
Authors: M Muenke; F Gurrieri; C Bay; D H Yi; A L Collins; V P Johnson; R C Hennekam; G B Schaefer; L Weik; M S Lubinsky Journal: Proc Natl Acad Sci U S A Date: 1994-08-16 Impact factor: 11.205
Authors: Sandra Mercier; Christèle Dubourg; Marion Belleguic; Laurent Pasquier; Philippe Loget; Josette Lucas; Claude Bendavid; Sylvie Odent Journal: Am J Med Genet C Semin Med Genet Date: 2010-02-15 Impact factor: 3.908