Amish lethal microcephaly

Summary

Amish lethal microcephaly (MONDO:0011790) is a disease caused by SLC25A19 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SLC25A19 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 37
• Phenotypes (HPO): 25

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000		Worldwide	Validated
Prevalence at birth	>1 / 1000	200	Specific population	Validated

Signs & symptoms

Clinical features (HPO)

25 HPO clinical features (Orphanet curated; top 25 by frequency):

HPO ID	Term	Frequency
HP:0000252	Microcephaly	Very frequent (80-99%)
HP:0000340	Sloping forehead	Very frequent (80-99%)
HP:0000347	Micrognathia	Very frequent (80-99%)
HP:0000648	Optic atrophy	Very frequent (80-99%)
HP:0000737	Irritability	Very frequent (80-99%)
HP:0001320	Cerebellar vermis hypoplasia	Very frequent (80-99%)
HP:0001522	Death in infancy	Very frequent (80-99%)
HP:0001942	Metabolic acidosis	Very frequent (80-99%)
HP:0001992	Organic aciduria	Very frequent (80-99%)
HP:0011344	Severe global developmental delay	Very frequent (80-99%)
HP:0011968	Feeding difficulties	Very frequent (80-99%)
HP:0000939	Osteoporosis	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001274	Agenesis of corpus callosum	Frequent (30-79%)
HP:0001339	Lissencephaly	Frequent (30-79%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0002414	Spina bifida	Frequent (30-79%)
HP:0002509	Limb hypertonia	Frequent (30-79%)
HP:0005968	Temperature instability	Frequent (30-79%)
HP:0000185	Cleft soft palate	Occasional (5-29%)
HP:0001376	Limitation of joint mobility	Occasional (5-29%)
HP:0001558	Decreased fetal movement	Occasional (5-29%)
HP:0002069	Bilateral tonic-clonic seizure	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0004331	Decreased skull ossification	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Amish lethal microcephaly
Mondo ID	MONDO:0011790
MeSH	C538247
OMIM	607196
Orphanet	99742
SNOMED CT	702437000
UMLS	C1846648
MedGen	375938
GARD	0008606
Is cancer (heuristic)	no

Also known as: Amish lethal microcephaly · MCPHA · microcephaly, Amish type

Data availability: 37 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › disorder of metabolite absorption and transport › disorder of vitamin and non-protein cofactor absorption and transport › disorder of thiamine metabolism and transport › thiamine-responsive dysfunction syndrome › Amish lethal microcephaly

Related subtypes (4): thiamine-responsive megaloblastic anemia syndrome, biotin-responsive basal ganglia disease, progressive demyelinating neuropathy with bilateral striatal necrosis, childhood encephalopathy due to thiamine pyrophosphokinase deficiency

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

37 retrieved; paginated sample, class counts are floors:

10 uncertain significance, 8 benign, 8 conflicting classifications of pathogenicity, 4 benign/likely benign, 3 pathogenic, 3 likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
692005	NM_001126121.2(SLC25A19):c.775-1G>C	MIF4GD-DT	Pathogenic	criteria provided, single submitter
30590	NM_001126121.2(SLC25A19):c.373G>A (p.Gly125Ser)	SLC25A19	Pathogenic	no assertion criteria provided
4269	NM_001126121.2(SLC25A19):c.530G>C (p.Gly177Ala)	SLC25A19	Pathogenic	no assertion criteria provided
692004	NM_001126121.2(SLC25A19):c.470C>T (p.Thr157Met)	SLC25A19	Likely pathogenic	criteria provided, single submitter
281113	NM_001126121.2(SLC25A19):c.797T>G (p.Met266Arg)	MIF4GD-DT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
596497	NM_001126121.2(SLC25A19):c.842T>G (p.Phe281Cys)	MIF4GD-DT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
197331	NM_001126121.2(SLC25A19):c.135T>A (p.Leu45=)	SLC25A19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
198247	NM_001126121.2(SLC25A19):c.590G>T (p.Ser197Ile)	SLC25A19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
285906	NM_001126121.2(SLC25A19):c.504C>T (p.Ser168=)	SLC25A19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
325067	NM_001126121.2(SLC25A19):c.246C>T (p.His82=)	SLC25A19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
597165	NM_001126121.2(SLC25A19):c.93G>A (p.Ala31=)	SLC25A19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
782161	NM_001126121.2(SLC25A19):c.155G>A (p.Arg52His)	SLC25A19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029820	NM_001126121.2(SLC25A19):c.779G>A (p.Arg260Gln)	MIF4GD-DT	Uncertain significance	criteria provided, multiple submitters, no conflicts
325064	NM_001126121.2(SLC25A19):c.*113G>C	MIF4GD-DT	Uncertain significance	criteria provided, single submitter
889454	NM_001126121.2(SLC25A19):c.*408C>T	MIF4GD-DT	Uncertain significance	criteria provided, single submitter
889455	NM_001126121.2(SLC25A19):c.*384C>T	MIF4GD-DT	Uncertain significance	criteria provided, single submitter
889457	NM_001126121.2(SLC25A19):c.*292A>G	MIF4GD-DT	Uncertain significance	criteria provided, single submitter
325068	NM_001126121.2(SLC25A19):c.20A>G (p.Lys7Arg)	SLC25A19	Uncertain significance	criteria provided, multiple submitters, no conflicts
436748	NM_001126121.2(SLC25A19):c.73T>G (p.Ser25Ala)	SLC25A19	Uncertain significance	criteria provided, multiple submitters, no conflicts
890720	NM_001126121.2(SLC25A19):c.476G>A (p.Arg159His)	SLC25A19	Uncertain significance	criteria provided, multiple submitters, no conflicts
891959	NM_001126121.2(SLC25A19):c.-170G>A	SLC25A19	Uncertain significance	criteria provided, single submitter
96021	NM_001126121.2(SLC25A19):c.622C>T (p.Pro208Ser)	SLC25A19	Uncertain significance	criteria provided, multiple submitters, no conflicts
130327	NM_001126121.2(SLC25A19):c.*2T>C	MIF4GD-DT	Benign	criteria provided, multiple submitters, no conflicts
130333	NM_001126121.2(SLC25A19):c.819G>A (p.Leu273=)	MIF4GD-DT	Benign	criteria provided, multiple submitters, no conflicts
325061	NM_001126121.2(SLC25A19):c.*437T>G	MIF4GD-DT	Benign	criteria provided, multiple submitters, no conflicts
325062	NM_001126121.2(SLC25A19):c.*274C>G	MIF4GD-DT	Benign	criteria provided, multiple submitters, no conflicts
325063	NM_001126121.2(SLC25A19):c.*200G>A	MIF4GD-DT	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
889456	NM_001126121.2(SLC25A19):c.*301C>T	MIF4GD-DT	Likely benign	criteria provided, single submitter
890139	NM_001126121.2(SLC25A19):c.*164G>A	MIF4GD-DT	Benign	criteria provided, single submitter
890140	NM_001126121.2(SLC25A19):c.*96G>C	MIF4GD-DT	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 2 · 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
SLC25A19	Strong	Autosomal recessive	Amish lethal microcephaly	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC25A19	Orphanet:217396	Progressive polyneuropathy with bilateral striatal necrosis
SLC25A19	Orphanet:99742	Amish lethal microcephaly

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC25A19	HGNC:14409	ENSG00000125454	Q9HC21	Mitochondrial thiamine pyrophosphate carrier	gencc,clinvar
MIF4GD-DT	HGNC:55335	ENSG00000263843		MIF4GD divergent transcript	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC25A19	Mitochondrial thiamine pyrophosphate carrier	Mitochondrial transporter mediating uptake of thiamine diphosphate into mitochondria.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC25A19	Other/Unknown	no		MCP, MCP_transmembrane, MCP_dom_sf
MIF4GD-DT	Other/Unknown	no

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left testis	1
right testis	1
testis	1
bone marrow cell	1
cortical plate	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC25A19	232	ubiquitous	marker	left testis, right testis, testis
MIF4GD-DT	130	broad	yes	male germ line stem cell (sensu Vertebrata) in testis, bone marrow cell, cortical plate

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC25A19	1,492
MIF4GD-DT	0

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC25A19	Q9HC21	85.23

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
Vitamin B1 (thiamin) metabolism	1	2284.0×	4e-04	SLC25A19

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
deoxynucleotide transport	1	16852.0×	2e-04	SLC25A19
thiamine pyrophosphate transmembrane transport	1	8426.0×	2e-04	SLC25A19
thiamine-containing compound metabolic process	1	5617.3×	2e-04	SLC25A19
thiamine diphosphate biosynthetic process	1	3370.4×	3e-04	SLC25A19

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC25A19	0	0
MIF4GD-DT	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	2	SLC25A19, MIF4GD-DT

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)
SLC25A19	0	—
MIF4GD-DT	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.