Novel B3GALTL mutation in Peters‐plus Syndrome

To the Editor: Peters-plus syndrome (MIM#261540) is a rare autosomal recessive genetic disorder including ocular features, systemic malformations, and variable degree of developmental delay. Ocular malformations concern the anterior chamber (98% of patients) and are mainly represented by Peters’ anomaly (73%) (1), which corresponds to corneal clouding and variable degrees of iridolenticulocorneal adhesions. Other features include short stature, broad extremities, cleft lip/palate, cardiac and genito-urinary malformations (1, 2). There is also a common facial dysmorphism comprising a round face, broad neck, thin and cupid bow upper lip, long philtrum, hypertelorism, short palpebral fissures, variable external ear anomalies and prominent forehead (1). In 2006, Lesnik Oberstein et al. identified the β1, 3-galactosyltransferase-like gene (B3GALTL) as the gene involved in Peters-plus syndrome (3). They found three different B3GALTL mutations with one, c.660+1G>A, representing 90% of the mutated alleles. These authors concluded that Peters-plus syndrome was thus a monogenic, primarily single-mutation syndrome. Reis et al. confirmed the role of B3GALTL in Peters-plus syndrome and identified two new mutations bringing the number of reported B3GALTL mutations to five (2). Further studies clearly established that B3GALTL mutations lead to a congenital disorder of glycosylation (4, 5). In this study, we screened two additional patients (patients 1 and 2) with clinically defined Petersplus syndrome for B3GALTL mutation. Their clinical features are summarized in Table 1, and craniofacial and extremities findings are illustrated in Fig. 1. We also included two patients with Peters’ anomaly and psychomotor delay but who did not meet other Peters-plus syndrome criteria. Two B3GALTL mutations were identified in the typical Peters-plus patients. Patient 1, originating from Sri Lanka, was compound heterozygous for the recurrent c.660+1G>A mutation and a novel missense mutation c.1178G>A (p.Gly393Glu) in exon 13 (Fig. 2a). This mutation was absent from a panel of 100 chromosomes from Caucasian controls, and predicted in silico to be probably damaging by Polyphen software (http://genetics.bwh. harvard.edu/pph/). This substituted glycine, located in the putative catalytic domain, has been shown to be one of the 12 most conserved amino acids during evolution of this protein orthologues (Fig. 2b), and to be located in one of the five most conserved functional domains of the enzyme (6). This is the first B3GALTL missense mutation to be involved in Peters-plus syndrome. Patient 2 was homozygous for the recently published c.459 + 1G>A splice site mutation. Parents of patients 1 and 2 were each shown to be heterozygous for one of the two mutations identified in their child. No causative mutations in B3GALTL were identified in patients who had Peters’ anomaly and psychomotor delay but without additional features of Peters-plus syndrome, confirming previous published data (2). Clinical presentation of patients published to date with B3GALTL mutations is summarized in Table 1. This table clearly shows that the major criteria of the Peters-plus syndrome, essentially always present, are anterior chamber anomalies (mainly Peters’ anomaly), growth retardation, and brachydactyly. Developmental delay is frequent, whereas cleft lip and/or palate, cardiac malformation, and external ear anomalies are observed in about half of the patients. Thus, although different B3GALTL mutations lead to Peters-plus syndrome, the clinical presentation seems to be uniform. No B3GALTL mutation was found in patients with an incomplete phenotype ((2), this report). Other glycosyltransferases or proteins modified by B3GALTL may be involved in these isolated or syndromic Peters’ anomalies, in which the patients do not fulfill all criteria for Peters-plus syndrome diagnosis. In conclusion, these results confirm the implication of B3GALTL in Peters-plus syndrome and support clinical homogeneity in patients with B3GALTL mutations. Furthermore, this is the first report of a B3GALTL missense deleterious mutation, showing that allelic heterogeneity is wider than initially described.