Pseudodiastrophic dysplasia expands the known phenotypic spectrum of defects in proteoglycan biosynthesis

Alicia B Byrne; Shuji Mizumoto; Peer Arts; Patrick Yap; Jinghua Feng; Andreas W Schreiber; Milena Babic; Sarah L King-Smith; Christopher P Barnett; Lynette Moore; Kazuyuki Sugahara; Hatice Mutlu-Albayrak; Gen Nishimura; Jan E Liebelt; Shuhei Yamada; Ravi Savarirayan; Hamish S Scott

doi:10.1136/jmedgenet-2019-106700

Pseudodiastrophic dysplasia expands the known phenotypic spectrum of defects in proteoglycan biosynthesis

J Med Genet. 2020 Jul;57(7):454-460. doi: 10.1136/jmedgenet-2019-106700. Epub 2020 Jan 27.

Authors

Alicia B Byrne^#^{1

2}, Shuji Mizumoto^#^{3

4

5}, Peer Arts¹, Patrick Yap^{6

7

8}, Jinghua Feng^{2

9}, Andreas W Schreiber^{2

9

10}, Milena Babic¹, Sarah L King-Smith^{1

11}, Christopher P Barnett^{12

13}, Lynette Moore^{13

14}, Kazuyuki Sugahara³, Hatice Mutlu-Albayrak¹⁵, Gen Nishimura¹⁶, Jan E Liebelt¹², Shuhei Yamada^{3

4}, Ravi Savarirayan^{6

17}, Hamish S Scott^{18

2

9

11

13}

Affiliations

¹ Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, South Australia, Australia.
² School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.
³ Department of Pathobiochemistry, Faculty of Pharmacy, Meijo University, Nagoya, Japan.
⁴ Research Center for Pathogenesis of Intractable Diseases, Meijo University, Nagoya, Japan.
⁵ Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
⁶ Victorian Clinical Genetics Service, Royal Children's Hospital, Melbourne, Victoria, Australia.
⁷ Genetic Health Service New Zealand (Northern Hub), Auckland, New Zealand.
⁸ Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
⁹ ACRF Genomics Facility, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, South Australia, Australia.
¹⁰ School of Biological Sciences, The University of Adelaide, Adelaide, South Australia, Australia.
¹¹ Australian Genomics Health Alliance, Melbourne, Victoria, Australia.
¹² South Australian Clinical Genetics Service, Women's and Children's Hospital, North Adelaide, South Australia, Australia.
¹³ School of Medicine, The University of Adelaide, Adelaide, South Australia, Australia.
¹⁴ Department of Surgical Pathology, Women's and Children's Hospital, SA Pathology, North Adelaide, South Australia, Australia.
¹⁵ Department of Pediatric Genetics, Cengiz Gökcek Obstetrics and Children's Hospital, Gaziantep, Turkey.
¹⁶ Department of Radiology, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.
¹⁷ Department of Paediatrics, The University of Melbourne, Melbourne, Victoria, Australia.
¹⁸ Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, South Australia, Australia hamish.scott@sa.gov.au.

^# Contributed equally.

Abstract

Background: Pseudodiastrophic dysplasia (PDD) is a severe skeletal dysplasia associated with prenatal manifestation and early lethality. Clinically, PDD is classified as a 'dysplasia with multiple joint dislocations'; however, the molecular aetiology of the disorder is currently unknown.

Methods: Whole exome sequencing (WES) was performed on three patients from two unrelated families, clinically diagnosed with PDD, in order to identify the underlying genetic cause. The functional effects of the identified variants were characterised using primary cells and human cell-based overexpression assays.

Results: WES resulted in the identification of biallelic variants in the established skeletal dysplasia genes, B3GAT3 (family 1) and CANT1 (family 2). Mutations in these genes have previously been reported to cause 'multiple joint dislocations, short stature, and craniofacial dysmorphism with or without congenital heart defects' ('JDSCD'; B3GAT3) and Desbuquois dysplasia 1 (CANT1), disorders in the same nosological group as PDD. Follow-up of the B3GAT3 variants demonstrated significantly reduced B3GAT3/GlcAT-I expression. Downstream in vitro functional analysis revealed abolished biosynthesis of glycosaminoglycan side chains on proteoglycans. Functional evaluation of the CANT1 variant showed impaired nucleotidase activity, which results in inhibition of glycosaminoglycan synthesis through accumulation of uridine diphosphate.

Conclusion: For the families described in this study, the PDD phenotype was caused by mutations in the known skeletal dysplasia genes B3GAT3 and CANT1, demonstrating the advantage of genomic analyses in delineating the molecular diagnosis of skeletal dysplasias. This finding expands the phenotypic spectrum of B3GAT3-related and CANT1-related skeletal dysplasias to include PDD and highlights the significant phenotypic overlap of conditions within the proteoglycan biosynthesis pathway.

Keywords: clinical genetics; molecular genetics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Dwarfism / genetics*
Dwarfism / pathology
Exome Sequencing
Female
Gene Expression Regulation / genetics
Genetic Predisposition to Disease
Glucuronosyltransferase / genetics*
Heart Defects, Congenital / genetics*
Heart Defects, Congenital / pathology
Hernia, Umbilical / genetics*
Hernia, Umbilical / pathology
Humans
Male
Mutation, Missense / genetics
Nucleotidases / genetics*
Phenotype
Pregnancy
Proteoglycans

Substances

Proteoglycans
B3GAT3 protein, human
Glucuronosyltransferase
CANT1 protein, human
Nucleotidases

Supplementary concepts

Pseudodiastrophic dysplasia