A deletion–insertion mutation in the phosphomannomutase 2 gene in an African American patient with congenital disorders of glycosylation‐Ia

Abstract

Congenital disorders of glycosylation (CDG) are a group of metabolic disorders with multisystemic involvement characterized by abnormalities in the synthesis of N-linked oligosaccharides. The most common form, CDG-Ia, resulting from mutations in the gene encoding the enzyme phosphomannomutase (PMM2), manifests with severe abnormalities in psychomotor development, dysmorphic features and visceral involvement. While this disorder is panethnic, we present the first cases of CDG-Ia identified in an African American family with two affected sisters. The proband had failure to thrive in infancy, hypotonia, ataxia, cerebellar hypoplasia and developmental delay. On examination, she also exhibited strabismus, inverted nipples and an atypical perineal fat distribution, all features characteristic of CDG-Ia. Direct sequencing demonstrated that the patient had a unique genotype, T237M/c.565-571 delAGAGAT insGTGGATTTCC. The novel deletion-insertion mutation, which was confirmed by subcloning and sequencing of each allele, introduces a stop codon 11 amino acids downstream from the site of the deletion. The presence of this deletion-insertion mutation at cDNA position 565 suggests that this site in the PMM2 gene may be a hotspot for chromosomal breakage.

Recognizable phenotypes in CDG

“…Other features reported in more than single patients include skin/peau d’orange in 7 (Clayton et al 1992; Vabres et al 1998; de Michelena et al 1999; Stark et al 2000; Noelle et al 2005; van de Kamp et al 2007), dysplastic ears (cupped, anteverted or crumpled) in 7 patients (Clayton et al 1992; Garel et al 1998; Tayebi et al 2002; Rudaks et al 2012; Resende et al 2014; Serrano et al 2015), low-set ears in 6 (Clayton et al 1992; Imtiaz et al 2000; Al-Maawali et al 2014; Serrano et al 2015), long philtrum in 6 (Harding et al 1988; Pavone et al 1996; Morava et al 2004; van de Kamp et al 2007; Kasapkara et al 2017), high-arched palate in 5 (Tayebi et al 2002; Bubel et al 2002; Işıkay et al 2014; Kasapkara et al 2017), long face in 3 (de Michelena et al 1999; Tayebi et al 2002), narrow/short palpebral fissures in 3 (Truin et al 2008; Işıkay et al 2014), epicanthal folds in 2 (Tayebi et al 2002; Enns et al 2002), prominent nose in 2 (Barone et al 2008; Thong et al 2009), and anteverted nares in 2 (Tayebi et al 2002; Morava et al 2004). Other features variably reported included hypertelorism in 2 (Edwards et al 2006; Kasapkara et al 2017), but hypotelorism in 2 (Pavone et al 1996); downslanted palpebral fissures in 3 (Clayton et al 1992; Bubel et al 2002), while others had upslanted palpebral fissures (Kjaergaard et al 2001; Brum et al 2008); flat nasal bridge in 5 (Harding et al 1988; Tayebi et al 2002; Thong et al 2009; Al-Maawali et al 2014; Kasapkara et al 2017) but high nasal bridge in 4 (Artigas et al 1998; Antoun et al 1999; Laplace et al 2003). A coarse face has been described in older adults (Bortot et al 2013; Barone et al 2015).…”

Congenital disorders of glycosylation: an update on defects affecting the biosynthesis of dolichol-linked oligosaccharides

“…Furthermore, symptoms of coagulopathy, hypotonia, cardiomyopathy, and gastrointestinal and hepatic problems are also frequently observed. Strong dysmorphic features including severe skeletal deformities are found in most cases [Mizugishi et al, 1999;Westphal et al, 2001a;Briones et al, 2002;Tayebi et al, 2002;Ono et al, 2003;Coman et al, 2005;Schollen et al, 2007;Vermeer et al, 2007;Wurm et al, 2007;Truin et al, 2008;Perez-Duenas et al, 2009;Thong et al, in press;Vega et al, 2009]. A mortality rate of over 20% within the first years of life is frequent in cases presenting with low residual PMM2 activity .…”

“…PMM2-CDG is the most frequent form of CDG in respect to the number of mutations identified to date, which sums up to 103 (Supp . Table S1) [Matthijs et al, 1997Mizugishi, et al, 1999;Grunewald et al, 2001;Westphal et al, 2001a;Briones et al, 2002;Schollen et al, 2002Schollen et al, , 2007Tayebi et al, 2002;Callewaert et al, 2003;Ono et al, 2003;Coman et al, 2005;Le Bizec et al, 2005;Vuillaumier-Barrot et al, 2006;Vermeer et al, 2007;Wurm et al, 2007;Truin et al, 2008;Perez-Duenas et al, 2009;Thong et al, in press;Vega et al, 2009]. Three of them (p.Q37H, p.E197A, and p.A233T) occur only in combination with two other heterozygous mutations and are therefore assumed to be single nucleotide polymorphisms.…”