The unfolding clinical spectrum of holoprosencephaly due to mutations in SHH, ZIC2, SIX3 and TGIF genes.
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 1.45 Mb 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.
Department of Clinical Genetics, School for Oncology & Developmental Biology (GROW), Maastricht UMC, The Netherlands. aimee.paulussen@gen.unimaas.nl
Aimée D C
AD
Paulussen
Constance T
CT
Schrander-Stumpel
Demis C J
DC
Tserpelis
Matteus K M
MK
Spee
Alexander P A
AP
Stegmann
Grazia M
GM
Mancini
Alice S
AS
Brooks
Margriet
M
Collée
Anneke
A
Maat-Kievit
Marleen E H
ME
Simon
Yolande
Y
van Bever
Irene
I
Stolte-Dijkstra
Wilhelmina S
WS
Kerstjens-Frederikse
Johanna C
JC
Herkert
Anthonie J
AJ
van Essen
Klaske D
KD
Lichtenbelt
Arie
A
van Haeringen
Mei L
ML
Kwee
Augusta M A
AM
Lachmeijer
Gita M B
GM
Tan-Sindhunata
Merel C
MC
van Maarle
Yvonne H J M
YH
Arens
Eric E J G L
EE
Smeets
Christine E
CE
de Die-Smulders
John J M
JJ
Engelen
Hubertus J
HJ
Smeets
Jos
J
Herbergs
D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D053823:Hedgehog Proteins / Q000235:genetics*; D016142:Holoprosencephaly / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D000097607:Homeobox Protein SIX3
D005136:Eye Proteins; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D000097607:Homeobox Protein SIX3; C509239:SHH protein, human; C097504:TGIF1 protein, human; C491812:ZIC2 protein, human