Multiple congenital anomalies-hypotonia-seizures syndrome 3

Summary

Multiple congenital anomalies-hypotonia-seizures syndrome 3 (MONDO:0014165) is a disease caused by PIGT (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PIGT (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 248
• Phenotypes (HPO): 71

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

71 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000248	Brachycephaly	Very frequent (80-99%)
HP:0000341	Narrow forehead	Very frequent (80-99%)
HP:0000343	Long philtrum	Very frequent (80-99%)
HP:0000348	High forehead	Very frequent (80-99%)
HP:0000486	Strabismus	Very frequent (80-99%)
HP:0000639	Nystagmus	Very frequent (80-99%)
HP:0000938	Osteopenia	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0003100	Slender long bone	Very frequent (80-99%)
HP:0005280	Depressed nasal bridge	Very frequent (80-99%)
HP:0010864	Intellectual disability, severe	Very frequent (80-99%)
HP:0011842	Abnormality of skeletal morphology	Very frequent (80-99%)
HP:0100704	Cerebral visual impairment	Very frequent (80-99%)
HP:0000079	Abnormality of the urinary system	Frequent (30-79%)
HP:0000121	Nephrocalcinosis	Frequent (30-79%)
HP:0000365	Hearing impairment	Frequent (30-79%)
HP:0000431	Wide nasal bridge	Frequent (30-79%)
HP:0000540	Hypermetropia	Frequent (30-79%)
HP:0000767	Pectus excavatum	Frequent (30-79%)
HP:0001627	Abnormal heart morphology	Frequent (30-79%)
HP:0002069	Bilateral tonic-clonic seizure	Frequent (30-79%)
HP:0002123	Generalized myoclonic seizure	Frequent (30-79%)
HP:0002150	Hypercalciuria	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0002705	High, narrow palate	Frequent (30-79%)
HP:0002714	Downturned corners of mouth	Frequent (30-79%)
HP:0002750	Delayed skeletal maturation	Frequent (30-79%)
HP:0003072	Hypercalcemia	Frequent (30-79%)
HP:0003282	Low alkaline phosphatase	Frequent (30-79%)
HP:0008676	Congenital megaureter	Frequent (30-79%)
HP:0009824	Upper limb undergrowth	Frequent (30-79%)
HP:0010818	Generalized tonic seizure	Frequent (30-79%)
HP:0012373	Abnormal eye physiology	Frequent (30-79%)
HP:0000107	Renal cyst	Occasional (5-29%)
HP:0000110	Renal dysplasia	Occasional (5-29%)
HP:0000272	Malar flattening	Occasional (5-29%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0000369	Low-set ears	Occasional (5-29%)
HP:0000483	Astigmatism	Occasional (5-29%)
HP:0000545	Myopia	Occasional (5-29%)
HP:0000582	Upslanted palpebral fissure	Occasional (5-29%)
HP:0000826	Precocious puberty	Occasional (5-29%)
HP:0000829	Hypoparathyroidism	Occasional (5-29%)
HP:0001272	Cerebellar atrophy	Occasional (5-29%)
HP:0001363	Craniosynostosis	Occasional (5-29%)
HP:0001382	Joint hypermobility	Occasional (5-29%)
HP:0001513	Obesity	Occasional (5-29%)
HP:0001631	Atrial septal defect	Occasional (5-29%)
HP:0001643	Patent ductus arteriosus	Occasional (5-29%)
HP:0001723	Restrictive cardiomyopathy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	multiple congenital anomalies-hypotonia-seizures syndrome 3
Mondo ID	MONDO:0014165
MeSH	C566367
OMIM	603530, 615398
Orphanet	369837
DOID	DOID:0080140
UMLS	C3809356
MedGen	815686
GARD	0017584
Is cancer (heuristic)	no

Also known as: congenital disorder of glycosylation due to PIGT deficiency · LFSS · MCAHS type 3 · MCAHS3 · multiple congenital anomalies-hypotonia-seizures syndrome 3 · multiple congenital anomalies-hypotonia-seizures syndrome type 3 · multiple congenital anomalies/dysmorphic syndrome-intellectual disability caused by mutation in PIGT · PIGT multiple congenital anomalies/dysmorphic syndrome-intellectual disability · PIGT-CDG

Data availability: 248 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › multiple congenital anomalies-hypotonia-seizures syndrome 3

Related subtypes (47): symphalangism, cartilage cancer, vertebral column disorder, patellar tendinitis, necrosis of ear ossicle, laryngeal cartilage cancer, ochronosis disorder, chondroma, periodontal disorder, posterior cranial fossa meningioma, anterior cranial fossa meningioma, middle cranial fossa meningioma, bone marrow disorder, cranial nodular fasciitis, flatfoot, bone disorder, skeletal tuberculosis, arthropathy, tooth disorder, primary basilar invagination, Brachymorphism-onychodysplasia-dysphalangism syndrome, cherubism, fibrodysplasia ossificans progressiva, Marfan syndrome, Buschke-Ollendorff syndrome, scalp defects-postaxial polydactyly syndrome, cartilage-hair hypoplasia, Teebi-Shaltout syndrome, short stature-auditory canal atresia-mandibular hypoplasia-skeletal anomalies syndrome, ossification of the posterior longitudinal ligament of the spine, temtamy preaxial brachydactyly syndrome, metaphyseal undermodeling, spondylar dysplasia, and overgrowth, Al-Gazali syndrome, brachydactyly-syndactyly syndrome, endocrine-cerebro-osteodysplasia syndrome, metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria, Rienhoff syndrome, Coffin-Siris syndrome, microcephaly-brachydactyly-kyphoscoliosis syndrome, cartilage development disorder, syndactyly, polydactyly, brachydactyly, sternal neoplasm, short stature, amelogenesis imperfecta, and skeletal dysplasia with scoliosis, skeletal ligament disorder, brachydactyly-syndactyly-oligodactyly syndrome

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

248 retrieved; paginated sample, class counts are floors:

102 likely benign, 93 uncertain significance, 16 conflicting classifications of pathogenicity, 10 pathogenic, 7 benign, 7 pathogenic/likely pathogenic, 7 benign/likely benign, 6 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1217438	NM_015937.6(PIGT):c.1043dup (p.Val349fs)	PIGT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1418074	NM_015937.6(PIGT):c.271C>T (p.Gln91Ter)	PIGT	Pathogenic	criteria provided, single submitter
143194	NM_015937.6(PIGT):c.1342C>T (p.Arg448Trp)	PIGT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
143195	NM_015937.6(PIGT):c.918_919insT (p.Val307fs)	PIGT	Pathogenic	no assertion criteria provided
2030623	NM_015937.6(PIGT):c.564del (p.Trp189fs)	PIGT	Pathogenic	criteria provided, single submitter
225546	NM_015937.6(PIGT):c.250G>T (p.Glu84Ter)	PIGT	Pathogenic	criteria provided, multiple submitters, no conflicts
2995955	NM_015937.6(PIGT):c.1043del (p.Pro348fs)	PIGT	Pathogenic	criteria provided, single submitter
372986	NM_015937.6(PIGT):c.988C>T (p.Arg330Ter)	PIGT	Pathogenic	criteria provided, multiple submitters, no conflicts
420919	NM_015937.6(PIGT):c.188-2A>G	PIGT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
440973	NM_015937.6(PIGT):c.1582G>A (p.Val528Met)	PIGT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
451026	NM_015937.6(PIGT):c.1079G>T (p.Gly360Val)	PIGT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
503770	NM_015937.6(PIGT):c.918dup (p.Val307fs)	PIGT	Pathogenic	criteria provided, multiple submitters, no conflicts
576071	NM_015937.6(PIGT):c.57del (p.Trp20fs)	PIGT	Pathogenic	criteria provided, single submitter
576072	NM_015937.6(PIGT):c.514C>T (p.Arg172Cys)	PIGT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
583283	NM_015937.6(PIGT):c.494-2A>G	PIGT	Pathogenic	criteria provided, multiple submitters, no conflicts
639214	NM_015937.6(PIGT):c.796C>T (p.Arg266Ter)	PIGT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
660514	NM_015937.6(PIGT):c.835C>T (p.Arg279Ter)	PIGT	Pathogenic	criteria provided, single submitter
2585406	NM_015937.6(PIGT):c.709G>C (p.Glu237Gln)	PIGT	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3359139	NM_015937.6(PIGT):c.17del (p.Pro6fs)	PIGT	Likely pathogenic	criteria provided, single submitter
3390855	NM_015937.6(PIGT):c.1520_1521insCTCTACA (p.Leu508fs)	PIGT	Likely pathogenic	criteria provided, single submitter
3780121	NM_015937.6(PIGT):c.1465_1466del (p.Phe492fs)	PIGT	Likely pathogenic	criteria provided, single submitter
619956	NM_015937.6(PIGT):c.1096G>T (p.Gly366Trp)	PIGT	Likely pathogenic	criteria provided, single submitter
64649	NM_015937.6(PIGT):c.547A>C (p.Thr183Pro)	PIGT	Likely pathogenic	criteria provided, single submitter
1029418	NM_015937.6(PIGT):c.1730dup (p.Leu578fs)	PIGT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1032713	NM_015937.6(PIGT):c.848A>T (p.Asp283Val)	PIGT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1363275	NM_015937.6(PIGT):c.1520G>A (p.Arg507Gln)	PIGT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2070333	NM_015937.6(PIGT):c.1502G>A (p.Gly501Asp)	PIGT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2075578	NM_015937.6(PIGT):c.886G>A (p.Val296Met)	PIGT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2162713	NM_015937.6(PIGT):c.70G>A (p.Glu24Lys)	PIGT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
252703	NM_015937.6(PIGT):c.1067G>A (p.Arg356Gln)	PIGT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
PIGT	Definitive	Autosomal recessive	multiple congenital anomalies-hypotonia-seizures syndrome 3	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PIGT	Orphanet:369837	Intellectual disability-seizures-hypophosphatasia-ophthalmic-skeletal anomalies syndrome

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
PIGT	HGNC:14938	ENSG00000124155	Q969N2	GPI-anchor transamidase component PIGT	gencc,clinvar
MIR6812	HGNC:50116	ENSG00000273555		microRNA 6812	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PIGT	GPI-anchor transamidase component PIGT	Component of the glycosylphosphatidylinositol-anchor (GPI-anchor) transamidase (GPI-T) complex that catalyzes the formation of the linkage between a proprotein and a GPI-anchor and participates in GPI anchored protein biosynthesis.

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)
PIGT	Other/Unknown	no		PIG-T
MIR6812	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
cardia of stomach	1
pylorus	1
stromal cell of endometrium	1
granulocyte	1
skeletal muscle tissue	1
vermiform appendix	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PIGT	253	ubiquitous	marker	cardia of stomach, stromal cell of endometrium, pylorus
MIR6812	101		yes	skeletal muscle tissue, granulocyte, vermiform appendix

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PIGT	1,295
MIR6812	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PIGT	Q969N2	4

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
Attachment of GPI anchor to uPAR	1	1268.9×	8e-04	PIGT

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
GPI anchored protein biosynthesis	1	2808.7×	0.001	PIGT
attachment of GPI anchor to protein	1	2106.5×	0.001	PIGT
GPI anchor biosynthetic process	1	495.6×	0.003	PIGT
neuron apoptotic process	1	185.2×	0.007	PIGT
neuron differentiation	1	100.3×	0.010	PIGT

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
PIGT	0	0
MIR6812	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
PIGT	1	Binding:1

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	PIGT, MIR6812

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)
PIGT	1	—
MIR6812	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.