Skeletal dysplasia
Gene: MMP9
Biallelic variants in MMP9 associated with autosomal recessive, metaphyseal anadysplasia type 2. Usually associated with a milder phenotype characterised by normal birth length, transitory bowing of the legs, spontaneous regression and disappearance of metaphyseal alterations during adolescence. Phenotype of MAD type 2 cases secondary to biallelic MMP13 gene mutations (more reported cases associated with this gene) similar to MMP9 associated cases.
MMP9-associated MAD type 2 cases reported so far:
x2 sibs from 1 consanguineous Pakistani family diagnosed postnatally with normal stature, genu varum, metaphyseal fraying during infancy (PMID 19615667)
x1 child from consanguineous family with homozygous nonsense variants diagnosed age 19 months with improvement of skeletal manifestations over a short period and by an early age (PMID 34407464)
x2 siblings from x1 non-consanguineous Jewish Caucasian family reported with more severe phenotype than other previously reported cases for MAD type 2 (PMID 28342220). Both siblings diagnosed during 2nd trimester with shortening of long bones. x1 fetus terminated at 19 weeks gestation - dysmorphic face including micrognathia, flattened nose, hypertelorism, short neck and hypoplastic lungs. 2nd liveborn female - reduced body length at birth (-4 SD), facial dysmorphism, cleft palate, anteriorly placed anus and other anomalies. No radiographic metaphyseal anomalies. Both children identified as having the same homozygous MMP9 missense variants. Authors acknowledge the phenotype is more severe than other previously reported cases of MAD type 2 associated with MMP9 or MMP13 gene variants. Some dispute regarding this prenatal case as detailed by PMID 34407464 such as possibility of an alternative skeletal dysplasia diagnosis (Desbuquois dypslasia type 2) and presence of 5 homozygotes in gnomad with the same missense variants - ?founder mutation.Created: 2 Dec 2021, 5:10 a.m. | Last Modified: 2 Dec 2021, 5:10 a.m.
Panel Version: 0.9993
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Metaphyseal anadysplasia 2, MIM# 613073
Publications
Gene: mmp9 has been classified as Green List (High Evidence).
Added phenotypes 613073METAPHYSEAL ANADYSPLASIA 2 for gene: MMP9 Publications for gene MMP9 were updated from 28342220; 19615667 to 28342220; 19615667
Added phenotypes 613073METAPHYSEAL ANADYSPLASIA 2 for gene: MMP9 Publications for gene MMP9 were updated from 19615667; 28342220 to 28342220; 19615667
Source Victorian Clinical Genetics Services was added to MMP9. Source Expert Review Green was added to MMP9. Mode of inheritance for gene MMP9 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Added phenotypes 613073METAPHYSEAL ANADYSPLASIA 2 for gene: MMP9 Publications for gene MMP9 were updated from 28342220; 19615667 to 19615667; 28342220 Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
gene: MMP9 was added gene: MMP9 was added to Skeletal dysplasia. Sources: Emory Genetics Laboratory,Expert list,NHS GMS,Radboud University Medical Center, Nijmegen,UKGTN,Expert Review Amber,Illumina TruGenome Clinical Sequencing Services Mode of inheritance for gene: MMP9 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MMP9 were set to 28342220; 19615667 Phenotypes for gene: MMP9 were set to Metaphyseal anadysplasia 2 613073