Homozygous missense VPS16 variant is associated with a novel disease, resembling mucopolysaccharidosis-plus syndrome in two siblings

Yıldız Y., Koşukcu C., Aygün D., Akçaboy M., Öztek Çelebi F. Z., Taşcı Yıldız Y., ...More

CLINICAL GENETICS, vol.100, no.3, pp.308-317, 2021 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 100 Issue: 3
  • Publication Date: 2021
  • Doi Number: 10.1111/cge.14002
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, CAB Abstracts, EMBASE, MEDLINE
  • Page Numbers: pp.308-317
  • Keywords: class C core vacuole, endosome tethering (CORVET), endolysosomal pathway, homotypic fusion and vacuole protein sorting (HOPS), intracellular trafficking, lysosomal storage disease, mucopolysaccharidosis-plus syndrome, vacuolar protein sorting, vesicular trafficking, VPS16, RENAL DYSFUNCTION, VPS33A, ARTHROGRYPOSIS, RECRUITMENT, BIOGENESIS, MUTATIONS, PHENOTYPE, COMPLEX, FUSION, GENE
  • Hacettepe University Affiliated: Yes


Disorders of intracellular trafficking are a group of inherited disorders, which often display multisystem phenotypes. Vacuolar protein sorting (VPS) subunit C, composed of VPS11, VPS18, VPS16, and VPS33A proteins, is involved in tethering of endosomes, lysosomes, and autophagosomes. Our group and others have previously described patients with a specific homozygous missense VPS33A variant, exhibiting a storage disease phenotype resembling mucopolysaccharidosis (MPS), termed "MPS-plus syndrome." Here, we report two siblings from a consanguineous Turkish-Arabic family, who have overlapping features of MPS and intracellular trafficking disorders, including short stature, coarse facies, developmental delay, peripheral neuropathy, splenomegaly, spondylar dysplasia, congenital neutropenia, and high-normal glycosaminoglycan excretion. Whole exome sequencing and familial segregation analyses led to the homozygous NM_022575.3:c.540G>T; p.Trp180Cys variant in VPS16 in both siblings. Multiple bioinformatic methods supported the pathogenicity of this variant. Different monoallelic null VPS16 variants and a homozygous missense VPS16 variant had been previously associated with dystonia. A biallelic intronic, probably splice-altering variant in VPS16, causing an MPS-plus syndrome-like disease has been very recently reported in two individuals. The siblings presented herein display no dystonia, but have features of a multisystem storage disorder, representing a novel MPS-plus syndrome-like disease, associated for the first time with VPS16 missense variants.