Disruption of ALX1 causes extreme microphthalmia and severe facial clefting: expanding the spectrum of autosomal-recessive ALX-related frontonasal dysplasia.
We present an autosomal-recessive frontonasal dysplasia (FND) characterized by bilateral extreme microphthalmia, bilateral oblique facial cleft, complete cleft palate, hypertelorism, wide nasal bridge with hypoplasia of the ala nasi, and low-set, posteriorly rotated ears in two distinct families. Using Affymetrix 250K SNP array genotyping and homozygosity mapping, we mapped this clinical entity to chromosome 12q21. In one of the families, three siblings were affected, and CNV analysis of the critical region showed a homozygous 3.7 Mb deletion containing the ALX1 (CART1) gene, which encodes the aristaless-like homeobox 1 transcription factor. In the second family we identified a homozygous donor-splice-site mutation (c.531+1G > A) in the ALX1 gene, providing evidence that complete loss of function of ALX1 protein causes severe disruption of early craniofacial development. Unlike loss of its murine ortholog, loss of human ALX1 does not result in neural-tube defects; however, it does severely affect the orchestrated fusion between frontonasal, nasomedial, nasolateral, and maxillary processes during early-stage embryogenesis. This study further expands the spectrum of the recently recognized autosomal-recessive ALX-related FND phenotype in humans.
Uz
Elif
E
Gene Mapping Laboratory, Department of Medical Genetics, Hacettepe University Medical Faculty, Sihhiye, Ankara, Turkey.
Alanay
Yasemin
Y
Aktas
Dilek
D
Vargel
Ibrahim
I
Gucer
Safak
S
Tuncbilek
Gokhan
G
von Eggeling
Ferdinand
F
Yilmaz
Engin
E
Deren
Ozgur
O
Posorski
Nicole
N
Ozdag
Hilal
H
Liehr
Thomas
T
Balci
Sevim
S
Alikasifoglu
Mehmet
M
Wollnik
Bernd
B
Akarsu
Nurten A
NA
D002972:Cleft Palate / Q000235:genetics*; D004423:Ear / Q000002:abnormalities; D005145:Face / Q000002:abnormalities; D018398:Homeodomain Proteins / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008850:Microphthalmos / Q000235:genetics*; D009139:Musculoskeletal Abnormalities / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D022821:RNA Splice Sites / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics
C489985:ALX1 protein, human; D018398:Homeodomain Proteins; D022821:RNA Splice Sites
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