CRPPA

Inheritance Pattern: AR

Disease ID:MONDO:0100530

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0018279

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0100530

Submitter: ClinGen

The relationship between *CRPPA*/*ISPD* and autosomal recessive myopathy caused by variation in CRPPA (muscular dystrophy-dystroglycanopathy 7A and LGMD 7C/type 2U included), has been evaluated using the ClinGen Clinical Validity Framework as of November, 2023. Lumping & Splitting: OMIM entities: AR Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7; AR Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 7. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we did not find a significant difference in the inheritance pattern or molecular mechanism in the above-mentioned disease entities. Therefore, the two disease entities have been lumped under "myopathy caused by variation in CRPPA". This association was made using case-level, segregation, and experimental data. The *CRPPA* gene is located on chromosome 7p21.2. The transcript referred to in the literature (NM_001101426.3) is 5742 bp long with 10 exons encoding a 451-amino acid protein. Thirteen pathogenic and likely pathogenic variants reported in humans with autosomal recessive limb girdle muscular dystrophy (AR-LGMD) are recorded in ClinVar, most of them being predicted loss of function variants such as nonsense, frameshift, deletion/duplication and splicing variants. Patients with LGMD due to *CRPPA* variants show symmetrical proximal muscle weakness with an age of onset usually in first or second decade, scapular winging, difficulty in walking and running with loss of ambulation in some, foot drop, mild cardiac and respiratory issues, increased serum creatine kinase levels, and a muscle biopsy showing dystrophic changes. *CRPPA*/*ISPD* was first reported in relation to muscular dystrophy-dystroglycanopathy in 2012 (Willer et al, PMID: 22522420, Roscioli et al, PMID: 22522421) and in relation to LGMD by Cirak et al (PMID:23288328). Summary of Case Level Data (12 points): The association is seen in at least 11 probands in 3 publications (PMID:23288328, 23390185, 22522420). Variants in the gene segregated with the disease in 4 additional family members. More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism for disease is expected to be biallelic mutations abolishing the initial step in laminin-binding glycan synthesis by disrupting dystroglycan O-mannosylation. Summary of Experimental Data (4 points): This gene-disease relationship is supported by animal models, cell models, expression studies, and rescue models. *CRPPA* encodes the Isoprenoid synthase domain containing protein (ISPD) also known as CDP-L-Ribitol Pyrophosphorylase A (CRPPA) protein that is part of the dystroglycan complex (PMID: 26923585). This protein participates in a biochemical reaction to produce CDP-ribitol which is a substrate of *FKTN* during the biosynthesis of the phosphorylated O-mannosyl trisaccharide, a carbohydrate structure present in alpha-dystroglycan (*DAG1*), which is required for binding laminin G-like domain-containing extracellular proteins with high affinity. Tokuoka et al. 2022 (PMID: 35422047) studied the ISPD-deficient mice showing that the Skeletal muscle phenotype of Myf5-Ispd-cKO mice showed muscular dystrophy (HP:0003560), necrotic and regenerating fibers (HP:0003713), central nucleation (HP:0003687), and fibrous connective tissue infiltration (HP:0100297). Tokuoka et al. 2022 (PMID: 35422047) also examined the ISPD-cKO mice gene replacement after 2 months (12 weeks of age). Western blot analysis revealed no ISPD protein signals in non-injected WT or cKO skeletal muscle, indicating that endogenous ISPD protein levels were below detectable levels in skeletal muscle. Conversely, the skeletal muscles of cKO mice treated with AAV9-MCK-hISPD displayed ISPD protein expression and recovered α-DG glycosylation. In addition, CDP-Rbo levels were dramatically higher in the AAV9-MCK-hISPD-treated skeletal muscles than in non-treated Myf5-Ispd-cKO muscle and several times higher than in non-treated WT skeletal muscle. In summary, this gene-disease relationship is definitive. 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 Muscular Dystrophies and Myopathies GCEP on December 12, 2024.

Inheritance Pattern: AR

Disease ID:MONDO:0000171

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0014474

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0013835

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0013835

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0013835

Submitter: Genomics England PanelApp