Submission Details

PMM2 was first reported in relation to autosomal recessive PMM2-congenital disorder of glycosylation in 1997 (Matthijs et al, PMID: 9140401). PMM2-congenital disorder of glycosylation (PMM2-CDG), also known as congenital disorder of glycosylation type 1a, and Jaeken syndrome, is the only disorder listed for PMM2 in OMIM (MIM#212065).

PMM2 encodes phosphomannomutase 2, an enzyme that converts mannose-6-phosphate into mannose-1- phosphate. Mannose-1-phosphate is a precursor of guanosine diphosphate mannose (GDP-Man) and dolichol-P-mannose (Dol-P-Man). Deficiency of GDP-Man and Dol-P-Man, due to loss of PMM2 activity, causes hypoglycosylation of numerous glycoproteins and results in a multisystemic disorder (Haeuptle and Hennet, 2009, PMID: 19862844).

PMM2-CDG is the most common disorder of N-linked glycosylation. Clinical findings are highly variable and range from severely affected infants to mildly affected adults (Lam and Krasnewich, 2021, PMID: 20301289). Symptoms in affected infants include axial hypotonia, inverted nipples, abnormal fat distribution, esotropia, developmental delay, failure to thrive, and cerebellar hypoplasia. About 20% of severely affected infants die before a year of age. Those who survive may develop ataxia, severe developmental delay, inability to walk, intellectual disability, seizures, stroke-like episodes, coagulopathy, retinitis pigmentosa, joint contractures, and skeletal deformities in childhood. Adults have stable intellectual disability, variable peripheral neuropathy, premature aging is observed, lack of secondary sexual development in females and decreased testicular volume in males, hypogonadotropic hypogonadism, and increased risk for deep venous thrombosis is increased (Lam and Krasnewich, 2021, PMID: 20301289). Diagnosis is established by established type I transferrin isoform analysis, genetic testing (biallelic variants in PMM2), and/or deficient phosphomannomutase enzyme activity (Lam and Krasnewich, 2021, PMID: 20301289).

There is a clear prenatal/neonatal phenotype associated with PMM2-CDG, evident in many probands demonstrating the gene-disease association. The most severe cases of PMM2-CDG are characterized by non-immune hydrops fetalis, which also stands as the predominant antenatal presentation for this condition. Concomitant observations include hydropic placenta, polyhydramnios, and potential mirror syndrome. Among all individuals presenting with hydrops fetalis, the longest reported survival was three months after birth. Additionally, antenatal examinations may reveal hypertrophic cardiomyopathy, cerebral and cerebellar anomalies—specifically ventriculomegaly, cerebellar hypoplasia or atrophy, and skeletal deformities. Currently, there is no known association between PMM2-CDG and early pregnancy loss (PMID: 16915591, 18203160, 19176971, 17307006, 34277356, 20638314).

Thirteen variants (eleven missense, one frameshift, and one intronic variant) that have been reported in eight probands in six publications (Westphal et al, 2001; PMID: 11715002; Schollen et al, 2007, PMID: 17307006; Wurm et al, 2007, PMID: 16941129; de la Morena-Barrio et al, 2012, PMID: 23082948; Bortot et al, 2013, PMID: 23988505; González-Domínguez et al, 2021, PMID: 34277356) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function. Of note, individuals with PMM2-CDG are typically compound heterozygous for one severe and one mild variant, and it is thought that being biallelic for a severe variant is incompatible with life. For example, the most common variant identified in individuals with PMM2-CDG, c.422G>A (p.Arg141His) (ClinVar Variation ID: 7706), results in almost complete deficiency of PMM2 activity in functional assays (Pirard et al, 1999, PMID: 10386614; Kjaergaard et al, 1999, PMID: 10602363; Yuste-Checa et al, 2015, PMID:26014514). While this variant is present in about 75% of individuals with PMM2 of central European ancestry, and it has a carrier frequency of 1 in 60 and 1 in 79 in the Danish and Dutch populations respectively, it has never been reported in the homozygous state, thus lacks Hardy-Weinberg equilibrium (Matthijs et al, 1998, PMID: 9497260; Kjaergaard et al, 1999, PMID: 10602363; Schollen et al, 2000, PMID: 10854097).

This gene-disease relationship is also supported by experimental evidence including the biochemical function of the gene product which is consistent with the phenotype observed in humans (Pirard et al, 1999, PMID: 10085245; Haeuptle and Hennet, 2009, PMID: 19862844), rescue of mannose metabolism defect by lentiviral transduction of PMM2-deficient human fibroblasts with wild type PMM2 (Chan et al, 2016, PMID: 27053713), features observed in a zebrafish model in which Pmm2 has been knocked down using siRNA (Cline et al, 2012, PMID: 22956764), recapitulation of features observed in humans in mice with knock-in missense variants Pmm2 p.Arg137His and p.Phe115Leu, which correspond to the most common variants in human patients, p.Arg141His and p.Phe119Leu (Chan et al, 2016, PMID: 27053713). Additional evidence is available in the literature but the maximum number of point for experimental evidence (6 points) has been reached.

In summary, there is definitive evidence supporting the relationship between PMM2 and autosomal recessive PMM2-congenital disorder of glycosylation. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Congenital Disorders of Glycosylation Gene Curation Expert Panel on June 9, 2023 (SOP Version 9).

PMM2 was first reported in relation to autosomal recessive PMM2-congenital disorder of glycosylation in 1997 (Matthijs et al, PMID: 9140401). PMM2-congenital disorder of glycosylation (PMM2-CDG), also known as congenital disorder of glycosylation type 1a, and Jaeken syndrome, is the only disorder listed for PMM2 in OMIM (MIM#212065).

PMM2 encodes phosphomannomutase 2, and enzyme that converts mannose-6-phosphate into mannose-1- phosphate. Mannose-1-phosphate is a precursor of guanosine diphosphate mannose (GDP-Man) and dolichol-P-mannose (Dol-P-Man). Deficiency of GDP-Man and Dol-P-Man, due to loss of PMM2 activity, causes hypoglycosylation of numerous glycoproteins and results in a multisystemic disorder (Haeuptle and Hennet, 2009, PMID: 19862844).

PMM2-CDG is the most common disorder of N-linked glycosylation. Clinical findings are highly variable and range from severely affected infants to mildly affected adults (Lam and Krasnewich, 2021, PMID: 20301289). Symptoms in affected infants include axial hypotonia, inverted nipples, abnormal fat distribution, esotropia, developmental delay, failure to thrive, and cerebellar hypoplasia. About 20% of severely affected infants die before a year of age. Those who survive may develop ataxia, severe developmental delay, inability to walk, intellectual disability, seizures, stroke-like episodes, coagulopathy, retinitis pigmentosa, joint contractures, and skeletal deformities in childhood. Adults have stable intellectual disability, variable peripheral neuropathy, premature aging is observed, lack of secondary sexual development in females and decreased testicular volume in males, hypogonadotropic hypogonadism, and increased risk for deep venous thrombosis is increased (Lam and Krasnewich, 2021, PMID: 20301289). Diagnosis is established by established type I transferrin isoform analysis, genetic testing (biallelic variants in PMM2), and/or deficient phosphomannomutase enzyme activity (Lam and Krasnewich, 2021, PMID: 20301289).

There is a clear prenatal/neonatal phenotype associated with PMM2-CDG, evident in many probands demonstrating the gene-disease association. The most severe cases of PMM2-CDG are characterized by non-immune hydrops fetalis, which also stands as the predominant antenatal presentation for this condition. Concomitant observations include hydropic placenta, polyhydramnios, and potential mirror syndrome. Among all individuals presenting with hydrops fetalis, the longest reported survival was three months after birth. Additionally, antenatal examinations may reveal hypertrophic cardiomyopathy, cerebral and cerebellar anomalies—specifically ventriculomegaly, cerebellar hypoplasia or atrophy, and skeletal deformities. Currently, there is no known association between PMM2-CDG and early pregnancy loss (PMID: 16915591, 18203160, 19176971, 17307006, 34277356, 20638314).

Thirteen variants (eleven missense, one frameshift, and one intronic variant) that have been reported in eight probands in six publications (Westphal et al, 2001; PMID: 11715002; Schollen et al, 2007, PMID: 17307006; Wurm et al, 2007, PMID: 16941129; de la Morena-Barrio et al, 2012, PMID: 23082948; Bortot et al, 2013, PMID: 23988505; González-Domínguez et al, 2021, PMID: 34277356) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function. Of note, individuals with PMM2-CDG are typically compound heterozygous for one severe and one mild variant, and it is thought that being biallelic for a severe variant is incompatible with life. For example, the most common variant identified in individuals with PMM2-CDG, c.422G>A (p.Arg141His) (ClinVar Variation ID: 7706), results in almost complete deficiency of PMM2 activity in functional assays (Pirard et al, 1999, PMID: 10386614; Kjaergaard et al, 1999, PMID: 10602363; Yuste-Checa et al, 2015, PMID:26014514). While this variant is present in about 75% of individuals with PMM2 of central European ancestry, and it has a carrier frequency of 1 in 60 and 1 in 79 in the Danish and Dutch populations respectively, it has never been reported in the homozygous state, thus lacks Hardy-Weinberg equilibrium (Matthijs et al, 1998, PMID: 9497260; Kjaergaard et al, 1999, PMID: 10602363; Schollen et al, 2000, PMID: 10854097).

This gene-disease relationship is also supported by experimental evidence including the biochemical function of the gene product which is consistent with the phenotype observed in humans (Pirard et al, 1999, PMID: 10085245; Haeuptle and Hennet, 2009, PMID: 19862844), rescue of mannose metabolism defect by lentiviral transduction of PMM2-deficient human fibroblasts with wild type PMM2 (Chan et al, 2016, PMID: 27053713), features observed in a zebrafish model in which Pmm2 has been knocked down using siRNA (Cline et al, 2012, PMID: 22956764), recapitulation of features observed in humans in mice with knock-in missense variants Pmm2 p.Arg137His and p.Phe115Leu, which correspond to the most common variants in human patients, p.Arg141His and p.Phe119Leu (Chan et al, 2016, PMID: 27053713). Additional evidence is available in the literature but the maximum number of point for experimental evidence (6 points) has been reached.

In summary, there is definitive evidence supporting the relationship between PMM2 and autosomal recessive PMM2-congenital disorder of glycosylation. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Congenital Disorders of Glycosylation Gene Curation Expert Panel on June 9, 2023 (SOP Version 9).