TY - JOUR
T1 - The unfolding clinical spectrum of holoprosencephaly due to mutations in SHH, ZIC2, SIX3 and TGIF genes
AU - Paulussen, Aimee D. C.
AU - Schrander-Stumpel, Constance T. R. M.
AU - Tserpelis, Demis C. J.
AU - Spee, Matteus K. M.
AU - Stegmann, Alexander P. A.
AU - Mancini, Grazia M. S.
AU - Brooks, Alice S.
AU - Collee, Margriet J.
AU - Maat-Kievit, Anneke
AU - Simon, Marleen E. H.
AU - van Bever, Yolande
AU - Stolte-Dijkstra, Irene
AU - Kerstjens-Frederikse, Wilhelmina S.
AU - Herkert, Johanna C.
AU - van Essen, Anthonie J.
AU - Lichtenbelt, Klaske D.
AU - van Haeringen, Arie
AU - Kwee, Mei L.
AU - Lachmeijer, Augusta M. A.
AU - Tan-Sindhunata, Gita M. B.
AU - van Maarle, Merel C.
AU - Arens, Yvonne H. J. M.
AU - Smeets, Eric E. J. G. L.
AU - de Die-Smulders, Christine E. M.
AU - Engelen, John J. M.
AU - Smeets, Hubertus J. M.
AU - Herbergs, Jos
PY - 2010/9/10
Y1 - 2010/9/10
N2 - Holoprosencephaly is a severe malformation of the brain characterized by abnormal formation and separation of the developing central nervous system. The prevalence is 1:250 during early embryogenesis, the live-born prevalence is 1:16 000. The etiology of HPE is extremely heterogeneous and can be teratogenic or genetic. We screened four known HPE genes in a Dutch cohort of 86 non-syndromic HPE index cases, including 53 family members. We detected 21 mutations (24.4%), 3 in SHH, 9 in ZIC2 and 9 in SIX3. Eight mutations involved amino-acid substitutions, 7 ins/del mutations, 1 frame-shift, 3 identical poly-alanine tract expansions and 2 gene deletions. Pathogenicity of mutations was presumed based on de novo character, predicted non-functionality of mutated proteins, segregation of mutations with affected family-members or combinations of these features. Two mutations were reported previously. SNP array confirmed detected deletions; one spanning the ZIC2/ZIC5 genes (approx. 100 kb) the other a 1.45Mb deletion including SIX2/SIX3 genes. The mutation percentage (24%) is comparable with previous reports, but we detected significantly less mutations in SHH: 3.5 vs 10.7% (P = 0.043) and significantly more in SIX3: 10.5 vs 4.3% (P = 0.018). For TGIF1 and ZIC2 mutation the rate was in conformity with earlier reports. About half of the mutations were de novo, one was a germ line mosaic. The familial mutations displayed extensive heterogeneity in clinical manifestation. Of seven familial index patients only two parental carriers showed minor HPE signs, five were completely asymptomatic. Therefore, each novel mutation should be considered as a risk factor for clinically manifest HPE, with the caveat of reduced clinical penetrance. European Journal of Human Genetics (2010) 18, 999-1005; doi:10.1038/ejhg.2010.70; published online 9 June 2010
AB - Holoprosencephaly is a severe malformation of the brain characterized by abnormal formation and separation of the developing central nervous system. The prevalence is 1:250 during early embryogenesis, the live-born prevalence is 1:16 000. The etiology of HPE is extremely heterogeneous and can be teratogenic or genetic. We screened four known HPE genes in a Dutch cohort of 86 non-syndromic HPE index cases, including 53 family members. We detected 21 mutations (24.4%), 3 in SHH, 9 in ZIC2 and 9 in SIX3. Eight mutations involved amino-acid substitutions, 7 ins/del mutations, 1 frame-shift, 3 identical poly-alanine tract expansions and 2 gene deletions. Pathogenicity of mutations was presumed based on de novo character, predicted non-functionality of mutated proteins, segregation of mutations with affected family-members or combinations of these features. Two mutations were reported previously. SNP array confirmed detected deletions; one spanning the ZIC2/ZIC5 genes (approx. 100 kb) the other a 1.45Mb deletion including SIX2/SIX3 genes. The mutation percentage (24%) is comparable with previous reports, but we detected significantly less mutations in SHH: 3.5 vs 10.7% (P = 0.043) and significantly more in SIX3: 10.5 vs 4.3% (P = 0.018). For TGIF1 and ZIC2 mutation the rate was in conformity with earlier reports. About half of the mutations were de novo, one was a germ line mosaic. The familial mutations displayed extensive heterogeneity in clinical manifestation. Of seven familial index patients only two parental carriers showed minor HPE signs, five were completely asymptomatic. Therefore, each novel mutation should be considered as a risk factor for clinically manifest HPE, with the caveat of reduced clinical penetrance. European Journal of Human Genetics (2010) 18, 999-1005; doi:10.1038/ejhg.2010.70; published online 9 June 2010
KW - Holoprosencephaly
KW - SHH
KW - SIX3
KW - ZIC2
KW - TGIF
KW - genotype-phenotype
U2 - 10.1038/ejhg.2010.70
DO - 10.1038/ejhg.2010.70
M3 - Article
C2 - 20531442
SN - 1018-4813
VL - 18
SP - 999
EP - 1005
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 9
ER -