Immunodeficiency 93 and hypertrophic cardiomyopathy

Summary

Immunodeficiency 93 and hypertrophic cardiomyopathy (MONDO:0030528) is a disease caused by FNIP1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: FNIP1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 7

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency 93 and hypertrophic cardiomyopathy
Mondo ID	MONDO:0030528
OMIM	619705
Orphanet	693647
DOID	DOID:0061063
UMLS	C5676899
MedGen	1804175
Is cancer (heuristic)	no

Also known as: IMD93 · immunodeficiency and hypertrophic cardiomyopathy

Data availability: 7 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › immunodeficiency disease › immunodeficiency 93 and hypertrophic cardiomyopathy

Related subtypes (94): B cell deficiency, T-cell immunodeficiency, complement deficiency, myalgic encephalomeyelitis/chronic fatigue syndrome, hypoproteinemia, hypercatabolic, X-linked lymphoproliferative syndrome, Wiskott-Aldrich syndrome, autosomal dominant form, immunodeficiency due to CD25 deficiency, immunodeficiency 67, primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency, immunodeficiency 35, pyogenic bacterial infections due to MyD88 deficiency, lymphoproliferative syndrome 1, FADD-related immunodeficiency, immunodeficiency 31B, Wiskott-Aldrich syndrome 2, cryptosporidiosis-chronic cholangitis-liver disease syndrome, idiopathic CD4 lymphocytopenia, immunodeficiency 23, DOCK2 deficiency, immunodeficiency 45, TFRC-related combined immunodeficiency, combined immunodeficiency, autoimmune hemolytic anemia-autoimmune thrombocytopenia-primary immunodeficiency syndrome, immunodeficiency due to selective anti-polysaccharide antibody deficiency, immunodeficiency 57, immunodeficiency 14b, autosomal recessive, immunodeficiency 98 with autoinflammation, X-linked, immunodeficiency 102, immunodeficiency 74, COVID-19-related, X-linked, immunodeficiency 66, immunodeficiency 80 with or without congenital cardiomyopathy, immunodeficiency 81, immunodeficiency 82 with systemic inflammation, immunodeficiency 84, immunodeficiency 85 and autoimmunity, immunodeficiency 86, immunodeficiency 87 and autoimmunity, immunodeficiency 88, immunodeficiency 89 and autoimmunity, immunodeficiency 91 and hyperinflammation, immunodeficiency 92, immunodeficiency 95, immunodeficiency 96, immunodeficiency 97 with autoinflammation, immunodeficiency 99 with hypogammaglobulinemia and autoimmune cytopenias, immunodeficiency 101 (varicella zoster virus-specific), immunodeficiency 75, immunodeficiency 76, immunodeficiency 106, susceptibility to viral infections, immunodeficiency 78 with autoimmunity and developmental delay, immunodeficiency 77, immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection, immunodeficiency 15a, immunodeficiency 60, immunodeficiency 62, immunodeficiency 63 with lymphoproliferation and autoimmunity, immunodeficiency 64, immunodeficiency 65, susceptibility to viral infections, immunodeficiency 69, immunodeficiency 70, immunodeficiency 72 with autoinflammation, GATA2 deficiency with susceptibility to MDS/AML, Shwachman-Diamond syndrome 1, immunodeficiency 53, immunodeficiency 11b with atopic dermatitis, IKBKG-related immunodeficiency with or without ectodermal dysplasia, FNIP1-associated syndrome, FASLG-related immunodeficiency, TNFRSF9-related immunodeficiency, DNAJC21-related Shwachman Diamond syndrome, IRF4-related immune disorder, PTEN harmartoma tumor syndrome with immune disorder, primary immunodeficiency due to calcium channel deficiency, chronic mucocutaneous candidiasis and connective tissue disease due to JNK1 haploinsufficiency, immune deficiency due to impaired neutrophil phagocytosis and migration, hatipoglu immunodeficiency syndrome, immunodeficiency 112, immunodeficiency 113 with autoimmunity and autoinflammation, immunodeficiency 114, folate-responsive, immunodeficiency 115 with autoinflammation, immunodeficiency 117, immunodeficiency 118, immunodeficiency 119, immunodeficiency 121 with autoinflammation, immunodeficiency 122, immunodeficiency 123 with HPV-related verrucosis, immunodeficiency 125, immunodeficiency 126, susceptibility to, immunodeficiency 127, immunodeficiency 128, immunodeficiency 132b, immunodeficiency 133 with ectodermal dysplasia with or without peripheral neuropathy, immunodeficiency 134 (Epstein-Barr virus-specific)

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

7 retrieved; paginated sample, class counts are floors:

6 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1335870	NM_133372.3(FNIP1):c.3353G>A (p.Ser1118Asn)	FNIP1	Pathogenic	no assertion criteria provided
1335871	NM_133372.3(FNIP1):c.1289del (p.His430fs)	FNIP1	Pathogenic	no assertion criteria provided
1335872	NM_133372.3(FNIP1):c.3218del (p.Leu1073fs)	FNIP1	Pathogenic	no assertion criteria provided
1335873	NM_133372.3(FNIP1):c.868C>T (p.Arg290Ter)	FNIP1	Pathogenic	criteria provided, single submitter
1335874	NM_133372.3(FNIP1):c.3306+1G>A	FNIP1	Pathogenic	no assertion criteria provided
1335875	NC_000005.9:g.(?130766131)(131044371_131044893)del	RAPGEF6	Pathogenic	no assertion criteria provided
3065520	NM_133372.3(FNIP1):c.454C>G (p.Arg152Gly)	FNIP1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
FNIP1	Strong	Autosomal recessive	immunodeficiency 93 and hypertrophic cardiomyopathy	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FNIP1	Orphanet:693647	Agammaglobulinemia-early-onset hypertrophic cardiomyopathy-neutropenia syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FNIP1	HGNC:29418	ENSG00000217128	Q8TF40	Folliculin-interacting protein 1	gencc,clinvar
RAPGEF6	HGNC:20655	ENSG00000158987	Q8TEU7	Rap guanine nucleotide exchange factor 6	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FNIP1	Folliculin-interacting protein 1	Binding partner of the GTPase-activating protein FLCN: involved in the cellular response to amino acid availability by regulating the non-canonical mTORC1 signaling cascade controlling the MiT/TFE factors TFEB and TFE3.
RAPGEF6	Rap guanine nucleotide exchange factor 6	Guanine nucleotide exchange factor (GEF) for Rap1A, Rap2A and M-Ras GTPases.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Scaffold/PPI	1	8.6×	0.225
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FNIP1	Other/Unknown	no		FNIP_fam, FNIP_N_dom, FNIP_mid_dom
RAPGEF6	Scaffold/PPI	no		RA_dom, cNMP-bd_dom, Ras-like_Gua-exchang_fac_N

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cardiac muscle of right atrium	1
left ventricle myocardium	1
myocardium	1
calcaneal tendon	1
corpus callosum	1
epithelial cell of pancreas	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FNIP1	257	ubiquitous	marker	cardiac muscle of right atrium, left ventricle myocardium, myocardium
RAPGEF6	258	ubiquitous	marker	corpus callosum, epithelial cell of pancreas, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FNIP1	2,490
RAPGEF6	2,135

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RAPGEF6	Q8TEU7	2
FNIP1	Q8TF40	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Amino acids regulate mTORC1	1	200.3×	0.005	FNIP1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of B cell apoptotic process	1	2106.5×	0.003	FNIP1
negative regulation of lysosome organization	1	2106.5×	0.003	FNIP1
positive regulation of microvillus assembly	1	1685.2×	0.003	RAPGEF6
regulation of pro-B cell differentiation	1	1685.2×	0.003	FNIP1
immature B cell differentiation	1	1203.7×	0.003	FNIP1
microvillus assembly	1	936.2×	0.003	RAPGEF6
B cell apoptotic process	1	702.2×	0.004	FNIP1
TOR signaling	1	383.0×	0.006	FNIP1
negative regulation of TOR signaling	1	280.9×	0.007	FNIP1
regulation of GTPase activity	1	255.3×	0.007	RAPGEF6
positive regulation of TOR signaling	1	247.8×	0.007	FNIP1
positive regulation of protein-containing complex assembly	1	168.5×	0.009	FNIP1
positive regulation of TORC1 signaling	1	147.8×	0.010	FNIP1
B cell differentiation	1	109.4×	0.012	FNIP1
Ras protein signal transduction	1	102.8×	0.012	RAPGEF6
cellular response to starvation	1	96.8×	0.012	FNIP1
protein localization to plasma membrane	1	54.4×	0.020	RAPGEF6
negative regulation of cell population proliferation	1	21.1×	0.050	FNIP1
negative regulation of transcription by RNA polymerase II	1	8.9×	0.110	FNIP1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FNIP1	0	0
RAPGEF6	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
FNIP1	3	Binding:3

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	FNIP1, RAPGEF6

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
FNIP1	3	—
RAPGEF6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.