A novel phenotype in N-glycosylation disorders: Gillessen-Kaesbach–Nishimura skeletal dysplasia due to pathogenic variants in ALG9

Abstract

A rare lethal autosomal recessive syndrome with skeletal dysplasia, polycystic kidneys and multiple malformations was first described by Gillessen-Kaesbach et al and subsequently by Nishimura et al. The skeletal features uniformly comprise a round pelvis, mesomelic shortening of the upper limbs and defective ossification of the cervical spine. We studied two unrelated families including three affected fetuses with Gillessen-Kaesbach-Nishimura syndrome using whole-exome and Sanger sequencing, comparative genome hybridization and homozygosity mapping. All affected patients were shown to have a novel homozygous splice variant NM_024740.2: c.1173+2T4A in the ALG9 gene, encoding alpha-1,2-mannosyltransferase, involved in the formation of the lipid-linked oligosaccharide precursor of N-glycosylation. RNA analysis demonstrated skipping of exon 10, leading to shorter RNA. Mass spectrometric analysis showed an increase in monoglycosylated transferrin as compared with control tissues, confirming that this is a congenital disorder of glycosylation (CDG). Only three liveborn children with ALG9-CDG have been previously reported, all with missense variants. All three suffered from intellectual disability, muscular hypotonia, microcephaly and renal cysts, but none had skeletal dysplasia. Our study shows that some pathogenic variants in ALG9 can present as a lethal skeletal dysplasia with visceral malformations as the most severe phenotype. The skeletal features overlap with that previously reported for ALG3-and ALG12-CDG, suggesting that this subset of glycosylation disorders constitutes a new diagnostic group of skeletal dysplasias.

Isolated polycystic liver disease genes define effectors of polycystin-1 function

“…This is the first instance of data supporting the hypothesis that PCLD may manifest in carriers of severe recessive diseases, particularly congenital disorders of glycosylation (50). Notably, recessive mutations in ALG9 cause CDG1L and are associated with polycystic kidneys (52,53). Heterozygous carriers of ALG9 mutations may manifest PCLD as well.…”

Further Delineation of the ALG9-CDG Phenotype

“…So far only six patients with an ALG9-related phenotype have been reported in the literature (Frank et al 2004;Tham et al 2015;Vleugels et al 2009;Weinstein et al 2005). In this paper we report four more patients.…”

Alu-Alu mediated intragenic duplications in IFT81 and MATN3 are associated with skeletal dysplasias

“…We used a customized 2 × 400 K comparative genomic hybridization array targeting 1989 genes, including genes involved in skeletal dysplasias, ciliopathies, intellectual disability, and malformation syndromes (Hofmeister et al., ; Pettersson et al., ; Tham et al., ). The array also included all known genes in the cilia proteome and was ordered from OGT (Oxford Gene Technologies, Oxfordshire, UK).…”