Hereditary elliptocytosis

Summary

Hereditary elliptocytosis (MONDO:0017319) is a disease (an umbrella term covering 5 Mondo subtypes) with 4 cohort genes and 2 clinical trials. Top therapeutic interventions include lactulose and polyethylene glycol 3350.

At a glance

• Prevalence: 1-5 / 10 000 (Worldwide) [Orphanet-validated]
• Umbrella term: 5 Mondo subtypes
• Cohort genes: 4
• ClinVar variants: 1
• Phenotypes (HPO): 23
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

23 HPO clinical features (Orphanet curated; top 23 by frequency):

HPO ID	Term	Frequency
HP:0001877	Abnormal erythrocyte morphology	Obligate (100%)
HP:0004445	Elliptocytosis	Frequent (30-79%)
HP:0005502	Increased red cell osmotic fragility	Frequent (30-79%)
HP:0000952	Jaundice	Occasional (5-29%)
HP:0001744	Splenomegaly	Occasional (5-29%)
HP:0001878	Hemolytic anemia	Occasional (5-29%)
HP:0001923	Reticulocytosis	Occasional (5-29%)
HP:0002904	Hyperbilirubinemia	Occasional (5-29%)
HP:0003265	Neonatal hyperbilirubinemia	Occasional (5-29%)
HP:0003546	Exercise intolerance	Occasional (5-29%)
HP:0004446	Stomatocytosis	Occasional (5-29%)
HP:0004447	Poikilocytosis	Occasional (5-29%)
HP:0004804	Congenital hemolytic anemia	Occasional (5-29%)
HP:0006579	Prolonged neonatal jaundice	Occasional (5-29%)
HP:0012378	Fatigue	Occasional (5-29%)
HP:0200042	Skin ulcer	Occasional (5-29%)
HP:0001081	Cholelithiasis	Very rare (<1-4%)
HP:0001789	Hydrops fetalis	Very rare (<1-4%)
HP:0001945	Fever	Very rare (<1-4%)
HP:0002007	Frontal bossing	Very rare (<1-4%)
HP:0002027	Abdominal pain	Very rare (<1-4%)
HP:0008897	Postnatal growth retardation	Very rare (<1-4%)
HP:0025143	Chills	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary elliptocytosis
Mondo ID	MONDO:0017319
MeSH	D004612
Orphanet	288
DOID	DOID:2373
ICD-10-CM	D58.1
ICD-11	679955609
NCIT	C35882
SNOMED CT	178935009
UMLS	C0013902
MedGen	41747
GARD	0006621
MedDRA	10014490
NORD	1935
Is cancer (heuristic)	no

Also known as: congenital elliptocytosis · Hashimoto Encephalopathy · HE · hereditary ovalocytosis · ovalocytosis

Data availability: 1 ClinVar variant · 4 GenCC gene-disease records.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › hematologic disorder › anemia › normocytic anemia › hemolytic anemia › hereditary elliptocytosis

Related subtypes (10): familial hemolytic anemia, Heinz body anemia, lethal hemolytic anemia-genital anomalies syndrome, hemolytic disease of the newborn with Kell alloimmunization, Shiga toxin-associated hemolytic uremic syndrome, hereditary stomatocytosis, autoimmune hemolytic anemia, 6-phosphogluconate dehydrogenase deficiency, non-autoimmune hemolytic anemia, paroxysmal nocturnal hemoglobinuria

Subtypes (5): elliptocytosis 2, southeast Asian ovalocytosis, hemolytic anemia with thermal sensitivity of red cells, elliptocytosis 1, elliptocytosis 3

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

1 retrieved; paginated sample, class counts are floors:

1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
221297	NM_001376013.1(EPB41):c.1071_1077del (p.Asn358fs)	EPB41	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 26 · 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
EPB41	Definitive	Semidominant	elliptocytosis 1	5
SPTA1	Strong	Autosomal dominant	elliptocytosis 2	13
SPTB	Strong	Autosomal recessive	elliptocytosis 3	7
GYPC	Supportive	Autosomal dominant	hereditary elliptocytosis

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EPB41	Orphanet:288	Hereditary elliptocytosis
SPTA1	Orphanet:288	Hereditary elliptocytosis
SPTA1	Orphanet:822	Hereditary spherocytosis
SPTB	Orphanet:288	Hereditary elliptocytosis
SPTB	Orphanet:822	Hereditary spherocytosis
GYPC	Orphanet:288	Hereditary elliptocytosis

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
EPB41	HGNC:3377	ENSG00000159023	P11171	Protein 4.1	gencc,clinvar
SPTA1	HGNC:11272	ENSG00000163554	P02549	Spectrin alpha chain, erythrocytic 1	gencc
SPTB	HGNC:11274	ENSG00000070182	P11277	Spectrin beta chain, erythrocytic	gencc
GYPC	HGNC:4704	ENSG00000136732	P04921	Glycophorin-C	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EPB41	Protein 4.1	Protein 4.1 is a major structural element of the erythrocyte membrane skeleton.
SPTA1	Spectrin alpha chain, erythrocytic 1	Spectrin is the major constituent of the cytoskeletal network underlying the erythrocyte plasma membrane.
SPTB	Spectrin beta chain, erythrocytic	Spectrin is the major constituent of the cytoskeletal network underlying the erythrocyte plasma membrane.
GYPC	Glycophorin-C	This protein is a minor sialoglycoprotein in human erythrocyte membranes.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 3 · 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	4.3×	0.404
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EPB41	Other/Unknown	no		FERM_domain, Ez/rad/moesin-like, SAB_dom
SPTA1	Scaffold/PPI	no		SH3_domain, Spectrin_repeat, EF_hand_dom
SPTB	Other/Unknown	no		Actinin_actin-bd_CS, CH_dom, Spectrin_repeat
GYPC	Other/Unknown	no		Glycophorin, Neurexin-like, Glycophorin-C

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
trabecular bone tissue	3
bone marrow	2
cerebellar cortex	1
cerebellar hemisphere	1
bone marrow cell	1
gastrocnemius	1
hindlimb stylopod muscle	1
muscle of leg	1
blood	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EPB41	261	ubiquitous	marker	trabecular bone tissue, cerebellar hemisphere, cerebellar cortex
SPTA1	147	tissue_specific	marker	trabecular bone tissue, bone marrow, bone marrow cell
SPTB	220	broad	marker	gastrocnemius, hindlimb stylopod muscle, muscle of leg
GYPC	269	ubiquitous	marker	blood, trabecular bone tissue, bone marrow

Protein interactions among cohort

Intra-cohort edges: 5.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EPB41	1,928
SPTA1	1,551
GYPC	1,098
SPTB	1,079

Intra-cohort edges

A	B	Sources
EPB41	GYPC	intact, string_interaction
EPB41	SPTA1	string_interaction
EPB41	SPTB	string_interaction
GYPC	SPTB	string_interaction
SPTA1	SPTB	intact, string_interaction

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SPTB	P11277	6
EPB41	P11171	3
SPTA1	P02549	3
GYPC	P04921	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interaction between L1 and Ankyrins	2	184.2×	8e-04	SPTA1, SPTB
NCAM signaling for neurite out-growth	2	135.9×	8e-04	SPTA1, SPTB
ER to Golgi Anterograde Transport	2	66.4×	0.001	SPTA1, SPTB
MAPK1/MAPK3 signaling	2	65.6×	0.001	SPTA1, SPTB
L1CAM interactions	2	60.1×	0.001	SPTA1, SPTB
COPI-mediated anterograde transport	2	54.9×	0.001	SPTA1, SPTB
MAPK family signaling cascades	2	51.4×	0.001	SPTA1, SPTB
Transport to the Golgi and subsequent modification	2	51.4×	0.001	SPTA1, SPTB
RAF/MAP kinase cascade	2	30.5×	0.003	SPTA1, SPTB
Asparagine N-linked glycosylation	2	30.1×	0.003	SPTA1, SPTB
Axon guidance	2	22.6×	0.005	SPTA1, SPTB
Nervous system development	2	21.5×	0.005	SPTA1, SPTB
Membrane Trafficking	2	18.5×	0.006	SPTA1, SPTB
Vesicle-mediated transport	2	17.4×	0.007	SPTA1, SPTB
Post-translational protein modification	2	9.6×	0.020	SPTA1, SPTB
Neurexins and neuroligins	1	49.2×	0.025	EPB41
Developmental Biology	2	7.2×	0.031	SPTA1, SPTB
Metabolism of proteins	2	6.2×	0.039	SPTA1, SPTB
Cell surface interactions at the vascular wall	1	23.8×	0.044	GYPC
Signal Transduction	2	5.1×	0.051	SPTA1, SPTB

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
actin filament capping	2	1021.3×	2e-05	SPTA1, SPTB
actin cytoskeleton organization	3	79.1×	2e-05	EPB41, SPTA1, SPTB
regulation of intestinal absorption	1	2808.7×	0.002	EPB41
porphyrin-containing compound biosynthetic process	1	1404.3×	0.003	SPTA1
positive regulation of protein localization to cell cortex	1	1123.5×	0.003	EPB41
lymphocyte homeostasis	1	624.1×	0.004	SPTA1
modification of postsynaptic actin cytoskeleton	1	468.1×	0.005	SPTB
plasma membrane organization	1	295.6×	0.007	SPTA1
regulation of calcium ion transport	1	267.5×	0.007	EPB41
cortical actin cytoskeleton organization	1	200.6×	0.008	EPB41
actomyosin structure organization	1	187.2×	0.008	EPB41
hemopoiesis	1	89.2×	0.014	SPTA1
positive regulation of T cell proliferation	1	86.4×	0.014	SPTA1
regulation of cell shape	1	41.0×	0.027	SPTA1
actin filament organization	1	39.6×	0.027	SPTA1
cell division	1	15.4×	0.064	EPB41

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EPB41	0	0
SPTA1	0	0
SPTB	0	0
GYPC	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
EPB41	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	4	EPB41, SPTA1, SPTB, GYPC

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
EPB41	1	—
SPTA1	0	—
SPTB	0	—
GYPC	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00723567	Not specified	COMPLETED	A Novel Mutation of the Spectrin Gene
NCT01923376	Not specified	WITHDRAWN	Hepatic Encephalopathy: Lactulose or Polyethylene Glycol (H.E.L.P.)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
LACTULOSE	4	1
POLYETHYLENE GLYCOL 3350	4	1