Fatal infantile hypertonic myofibrillar myopathy

Summary

Fatal infantile hypertonic myofibrillar myopathy (MONDO:0013472) is a disease caused by CRYAB (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CRYAB (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 30

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		11	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	fatal infantile hypertonic myofibrillar myopathy
Mondo ID	MONDO:0013472
OMIM	613869
Orphanet	280553
DOID	DOID:0080309
UMLS	C5190691
MedGen	1684001
GARD	0017296
Is cancer (heuristic)	no

Also known as: fatal infantile hypertonic myofibrillar myopathy

Data availability: 30 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › skeletal muscle disorder › myopathy › congenital myopathy › congenital structural myopathy › myofibrillar myopathy › fatal infantile hypertonic myofibrillar myopathy

Related subtypes (12): central core myopathy, myofibrillar myopathy 1, myofibrillar myopathy 3, myofibrillar myopathy 4, myofibrillar myopathy 5, myofibrillar myopathy 6, myofibrillar myopathy 7, myofibrillar myopathy 8, myofibrillar myopathy 11, myofibrillar myopathy 10, myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy, myopathy, myofibrillar, 13, with rimmed vacuoles

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

30 retrieved; paginated sample, class counts are floors:

18 uncertain significance, 7 conflicting classifications of pathogenicity, 3 benign, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
178013	NM_001289808.2(CRYAB):c.116C>T (p.Pro39Leu)	CRYAB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
302430	NM_001289808.2(CRYAB):c.*38G>C	CRYAB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
302431	NM_001289808.2(CRYAB):c.375A>C (p.Pro125=)	CRYAB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
38963	NM_001289808.2(CRYAB):c.343del (p.Ser115fs)	CRYAB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
41926	NM_001289808.2(CRYAB):c.460G>A (p.Gly154Ser)	CRYAB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
44232	NM_001289808.2(CRYAB):c.152C>T (p.Pro51Leu)	CRYAB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
44236	NM_001289808.2(CRYAB):c.3G>A (p.Met1Ile)	CRYAB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1044759	NM_001289808.2(CRYAB):c.37C>A (p.Pro13Thr)	CRYAB	Uncertain significance	criteria provided, multiple submitters, no conflicts
1410499	NM_001289808.2(CRYAB):c.319C>T (p.Arg107Cys)	CRYAB	Uncertain significance	criteria provided, multiple submitters, no conflicts
1507716	NM_001289808.2(CRYAB):c.362A>G (p.Lys121Arg)	CRYAB	Uncertain significance	criteria provided, multiple submitters, no conflicts
201688	NM_001289808.2(CRYAB):c.16C>T (p.His6Tyr)	CRYAB	Uncertain significance	criteria provided, multiple submitters, no conflicts
2582676	NM_001289808.2(CRYAB):c.327T>G (p.Asp109Glu)	CRYAB	Uncertain significance	criteria provided, single submitter
302428	NM_001289808.2(CRYAB):c.*107A>G	CRYAB	Uncertain significance	criteria provided, single submitter
302432	NM_001289808.2(CRYAB):c.102G>T (p.Glu34Asp)	CRYAB	Uncertain significance	criteria provided, multiple submitters, no conflicts
393088	NM_001289808.2(CRYAB):c.367C>T (p.Arg123Trp)	CRYAB	Uncertain significance	criteria provided, multiple submitters, no conflicts
41925	NM_001289808.2(CRYAB):c.470G>A (p.Arg157His)	CRYAB	Uncertain significance	criteria provided, multiple submitters, no conflicts
569482	NM_001289808.2(CRYAB):c.65G>A (p.Arg22His)	CRYAB	Uncertain significance	criteria provided, multiple submitters, no conflicts
571646	NM_001289808.2(CRYAB):c.115C>G (p.Pro39Ala)	CRYAB	Uncertain significance	criteria provided, multiple submitters, no conflicts
643345	NM_001289808.2(CRYAB):c.275A>G (p.Lys92Arg)	CRYAB	Uncertain significance	criteria provided, multiple submitters, no conflicts
657190	NM_001289808.2(CRYAB):c.115C>T (p.Pro39Ser)	CRYAB	Uncertain significance	criteria provided, multiple submitters, no conflicts
657757	NM_001289808.2(CRYAB):c.119C>T (p.Thr40Met)	CRYAB	Uncertain significance	criteria provided, multiple submitters, no conflicts
810752	NM_001289808.2(CRYAB):c.482T>C (p.Ile161Thr)	CRYAB	Uncertain significance	criteria provided, multiple submitters, no conflicts
877466	NM_001289808.2(CRYAB):c.*60G>A	CRYAB	Uncertain significance	criteria provided, single submitter
879070	NM_001289808.2(CRYAB):c.176G>A (p.Ser59Asn)	CRYAB	Uncertain significance	criteria provided, single submitter
964348	NM_001289808.2(CRYAB):c.31C>G (p.Arg11Gly)	CRYAB	Uncertain significance	criteria provided, multiple submitters, no conflicts
302433	NM_001289808.2(CRYAB):c.-21C>T	CRYAB	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
419895	NM_001289808.2(CRYAB):c.324+13dup	CRYAB	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
44233	NM_001289808.2(CRYAB):c.165G>A (p.Leu55=)	CRYAB	Benign	criteria provided, multiple submitters, no conflicts
44234	NM_001289808.2(CRYAB):c.324+4T>G	CRYAB	Benign	criteria provided, multiple submitters, no conflicts
44239	NM_001289808.2(CRYAB):c.60C>T (p.Pro20=)	CRYAB	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 6 · 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
CRYAB	Definitive	Autosomal dominant	myofibrillar myopathy 2	16

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CRYAB	Orphanet:154	Familial isolated dilated cardiomyopathy
CRYAB	Orphanet:280553	Fatal infantile hypertonic myofibrillar myopathy
CRYAB	Orphanet:399058	Alpha-B crystallin-related late-onset myopathy
CRYAB	Orphanet:441452	Early-onset lamellar cataract
CRYAB	Orphanet:98991	Early-onset nuclear cataract
CRYAB	Orphanet:98993	Early-onset posterior polar cataract

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CRYAB	HGNC:2389	ENSG00000109846	P02511	Alpha-crystallin B chain	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CRYAB	Alpha-crystallin B chain	May contribute to the transparency and refractive index of the lens.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CRYAB	Other/Unknown	no		Alpha-crystallin/sHSP_animal, A-crystallin/Hsp20_dom, Alpha-crystallin_N

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cardiac ventricle	1
left ventricle myocardium	1
middle frontal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CRYAB	289	ubiquitous	marker	middle frontal gyrus, left ventricle myocardium, cardiac ventricle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CRYAB	3,368

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CRYAB	P02511	21

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 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
HSF1-dependent transactivation	1	317.2×	0.003	CRYAB

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
microtubule polymerization or depolymerization	1	16852.0×	0.001	CRYAB
negative regulation of intracellular transport	1	5617.3×	0.002	CRYAB
regulation of programmed cell death	1	2808.7×	0.002	CRYAB
apoptotic process involved in morphogenesis	1	2808.7×	0.002	CRYAB
tubulin complex assembly	1	1685.2×	0.003	CRYAB
negative regulation of amyloid fibril formation	1	1296.3×	0.003	CRYAB
negative regulation of reactive oxygen species metabolic process	1	936.2×	0.004	CRYAB
stress-activated MAPK cascade	1	702.2×	0.004	CRYAB
protein refolding	1	624.1×	0.004	CRYAB
cellular response to gamma radiation	1	601.9×	0.004	CRYAB
response to hydrogen peroxide	1	468.1×	0.005	CRYAB
negative regulation of protein-containing complex assembly	1	455.5×	0.005	CRYAB
response to heat	1	421.3×	0.005	CRYAB
lens development in camera-type eye	1	374.5×	0.005	CRYAB
glutathione metabolic process	1	351.1×	0.005	CRYAB
muscle contraction	1	208.1×	0.007	CRYAB
response to estradiol	1	198.3×	0.007	CRYAB
muscle organ development	1	166.8×	0.008	CRYAB
negative regulation of cell growth	1	144.0×	0.009	CRYAB
protein folding	1	103.4×	0.012	CRYAB
response to hypoxia	1	95.8×	0.012	CRYAB
negative regulation of gene expression	1	69.1×	0.016	CRYAB
protein stabilization	1	66.9×	0.016	CRYAB
negative regulation of apoptotic process	1	34.8×	0.030	CRYAB
negative regulation of DNA-templated transcription	1	31.6×	0.032	CRYAB

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CRYAB	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
CRYAB	13	Binding:13

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	CRYAB

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CRYAB	13	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.