Prenatal course of metaphyseal anadysplasia associated with homozygous mutation in MMP9 identified by exome sequencing.
Metaphyseal anadysplasia (MANDP) is a rare autosomal recessive form of skeletal dysplasia characterized by normal length at birth and transitory bowing of the legs. Although several families with MANDP have been reported, homozygous mutations in the matrix metalloproteinase type 9 (MMP9) gene have been described in only one consanguineous family, and thus the pre and postnatal phenotypic spectrum is still obscure. A clinically similar but more severe type is caused by autosomal-dominant inheritance and is caused by mutations in matrix metalloproteinase type 13 gene (MMP13). Here, we report the prenatal and early postnatal course of two affected sib fetuses with early sonographic evidence of long bone shortening and postnatally no metaphyseal changes. Whole-exome sequencing revealed homozygous mutation in MMP9 in both fetuses suggesting a diagnosis of MANDP. We propose that MANDP should be considered in pregnancies with early prenatal shortening of the long bones without associated finding of lethal skeletal dysplasias. In addition, the finding of homozygous mutation in non-consanguineous parents of Jewish-Caucasus ancestry may suggest unawareness of such relation or the occurrence of a founder mutation in this gene.
Medical Genetics Institute, Meir Medical Center, Kfar Saba, Israel.|Department of Obstetrics and Gynecology, Meir Medical Center, Kfar Saba, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
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http://orcid.org/0000-0002-6899-9223
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Sharony
Rappaport Faculty of Medicine, Technion Israeli Institute of Technology, Haifa, Israel.|Genetics Clinic, Assuta Medical Center, Haifa, Israel.
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Borochowitz
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Raphael Recanati Genetics Institute, Rabin Medical Center, Beilinson Campus, Petah Tikva 4941492, Israel.|Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petah Tikva 49202, Israel.
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Cohen
Medical Genetics Institute, Meir Medical Center, Kfar Saba, Israel.
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Shtorch-Asor
Medical Genetics Institute, Meir Medical Center, Kfar Saba, Israel.
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Rosenfeld
Clinical Operations, Variantyx, Inc, Herzliya, Israel.
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Modai
Medical Genetics Institute, Meir Medical Center, Kfar Saba, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
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http://orcid.org/0000-0002-3973-586X
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Reinstein
D000025:Abortion, Eugenic; D059472:Exome; D005260:Female; D015870:Gene Expression; D006720:Homozygote; D006801:Humans; D007223:Infant; D017880:Limb Deformities, Congenital / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D009154:Mutation; D010009:Osteochondrodysplasias / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D011296:Prenatal Diagnosis; D017422:Sequence Analysis, DNA; D035781:Siblings
C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
MMP9; exome; metaphyseal anadysplasia; prenatal diagnosis; skeletal dysplasia