Submission Details

LUMPING AND SPLITTING CONSIDERATIONS:

Stormorken Syndrome. OMIM: 185070; MONDO:0008497 Myopathy, tubular aggregate 1. OMIM: 160565; MONDO:0008051

Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanisms, inheritance pattern and phenotypic variability between these two phenotypes. Variants in the STIM1 gene have been observed in individuals with Stormorken Syndrome (SS) and tubular aggregate myopathy (TAM). The inheritance of SS and TAM is autosomal dominant. SS and TAM form a clinical continuum with heterogeneous disease severity and age of onset, characterized by muscle weakness, myalgia and additional multi-systemic signs such as miosis, thrombocytopenia, defective platelet function (impaired secretion of platelet granules, impaired aggregation, increased annexin V binding to platelet phosphatidylserine), hypocalcemia, asplenia, ichthyosis, short stature that can occur with variable degree. All patients show elevated serum creatine kinase. The full penetrance of the phenotype is referred as SS. Therefore, all of the disease entities have been lumped into one disease entity, Stormorken Syndrome.

On the contrary, we found differences in molecular mechanism, inheritance pattern and phenotypic variability with Immunodeficiency type 10, OMIM:612783, MONDO:0014260. Immunodeficiency type 10 is autosomal recessive and the molecular mechanism is homozygous loss of function. Moreover, patients show myopathy and muscular hypotonia together with an immunodeficiency phenotype that is related only to Immunodeficiency type 10. Therefore, we have split curation of Stormorken syndrome from curation of Immunodeficiency type 10. STIM1 is a Ca2+ sensor and senses the luminal Ca2+ concentration. Upon Ca2+ store depletion, STIM1 unfolds, oligomerizes, and activates Ca2+ release-activated Ca2+ (CRAC) channels such as ORAI1 at the plasma membrane, thus stimulating store-operated calcium entry (SOCE).

STIM1 was first reported in relation to SS in 2013 (Bohm et al., PMID 23332920) in patients with a typical TAM phenotype and in 2014 by two groups independently (Misceo et al., PMID 24619930; Nesin et al., PMID 24591628) in patients with the full SS phenotype. Another phenotype, called the York platelet syndrome (YPS) and described in 2003 (White JG, PMID 12745453), has been recognized later to be actually the SS (Markello et al., PMID 25577287).

At least 17 unique variants (16 missense and 1 frameshift) have been reported in humans. The most common variant is p.Arg304Trp. The mechanism for disease is heterozygous gain of function. Evidence supporting this gene-disease relationship includes genetic evidences (case-level data) and experimental evidences (functional evidence of biochemical functions, functional alteration in non-patient cells and patient cells, non-human model organisms that replicate the disease).

Summary of Case Level Data: 12 POINTS Variants in this gene have been reported in at least 24 probands in 13 publications (PMIDs: 28624464, 27876257, 23332920, 25326555, 31448844, 25953320, 29356264, 24591628, 27066587, 24619930, 25577287, 24570283, 31448844). More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached.

Summary of Experimental Data: 5 POINTS This gene-disease association is supported by in vitro functional assays and mouse models. Zhang et al. showed that STIM1 migrates from endoplasmic-reticulum like sites to the plasma membrane upon depletion of the Ca2+ store. Thus they propose that STIM1 is a Ca2+ sensor that translocates upon store depletion to the plasma membrane to activate CRAC channels (PMID: 16208375). Non-patient cells (murine myoblasts or cell lines) transfected with plasmids coding for different mutant STIM1 proteins show STIM1 clustering and impairment of Ca2+ sensing with a significantly higher basal cytoplasmic Ca2+ level and higher cytoplasmic Ca2+ influx (PMID: 23332920, supported by PMIDs 25326555, 31448844, 27876257, 27066587). Similar results were obtained by culturing fibroblasts from SS patients (PMID: 31448844). A mouse model expressing mutant (R304W) STIM1 recapitulates the characteristics of SS patients with muscle weakness, thrombocytopenia, prolonged bleeding time, growth delay, splenomegaly, abnormality of eye movement, skin irritations, hypocalcemia, increased serum creatine kinase and impaired Ca2+ homeostasis (PMID 30576443, supported by PMID 30390422).

In summary, STIM1 is definitively associated with Stormorken syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

This classification was approved by the ClinGen Hemostasis Thrombosis Working Group on 04/22/2020 (SOP Version 7).