holoprosencephaly 13, X-linked

Summary

holoprosencephaly 13, X-linked (MONDO:0026763) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 21

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	holoprosencephaly 13, X-linked
Mondo ID	MONDO:0026763
OMIM	301043
DOID	DOID:0060954
UMLS	C5393308
MedGen	1714826
GARD	0025490
Is cancer (heuristic)	no

Also known as: holoprosencephaly 13, X-linked, X-linked recessive, X-linked dominant · HPE13

Data availability: 21 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › holoprosencephaly › holoprosencephaly 13, X-linked

Related subtypes (16): holoprosencephaly 3, holoprosencephaly 4, holoprosencephaly 2, holoprosencephaly 1, holoprosencephaly 6, holoprosencephaly 8, holoprosencephaly 7, chromosome 1q41-q42 deletion syndrome, holoprosencephaly 11, microform holoprosencephaly, lobar holoprosencephaly, alobar holoprosencephaly, holoprosencephaly 14, holoprosencephaly 12 with or without pancreatic agenesis, semilobar holoprosencephaly, holoprosencephaly 10

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

21 retrieved; paginated sample, class counts are floors:

8 pathogenic, 4 benign/likely benign, 4 uncertain significance, 2 likely pathogenic, 1 benign, 1 conflicting classifications of pathogenicity, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1326915	NM_001042750.2(STAG2):c.1412_1416+9del	STAG2	Pathogenic	criteria provided, single submitter
2441833	NM_001042750.2(STAG2):c.867del (p.Phe289fs)	STAG2	Pathogenic	criteria provided, single submitter
4279014	NM_001042750.2(STAG2):c.3332dup (p.His1111fs)	STAG2	Pathogenic	criteria provided, single submitter
4468895	NM_001042750.2(STAG2):c.3053+2T>C	STAG2	Pathogenic	criteria provided, single submitter
4819118	NM_001042750.2(STAG2):c.2096+2T>A	STAG2	Pathogenic	criteria provided, single submitter
623239	NM_001042750.2(STAG2):c.205C>T (p.Arg69Ter)	STAG2	Pathogenic	no assertion criteria provided
864831	NM_001042750.2(STAG2):c.3034C>T (p.Arg1012Ter)	STAG2	Pathogenic	criteria provided, multiple submitters, no conflicts
864832	NM_001042750.2(STAG2):c.436C>T (p.Arg146Ter)	STAG2	Pathogenic	no assertion criteria provided
2584592	NM_001042750.2(STAG2):c.3222dup (p.Ser1075fs)	STAG2	Likely pathogenic	criteria provided, single submitter
4294532	NM_001042750.2(STAG2):c.1068T>G (p.Tyr356Ter)	STAG2	Likely pathogenic	criteria provided, single submitter
1900255	NM_001042750.2(STAG2):c.22C>A (p.Pro8Thr)	STAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1363782	NM_001042750.2(STAG2):c.3538A>G (p.Met1180Val)	STAG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2431611	NM_001042750.2(STAG2):c.1680G>A (p.Arg560=)	STAG2	Uncertain significance	criteria provided, single submitter
3236420	NM_001042750.2(STAG2):c.363T>A (p.Phe121Leu)	STAG2	Uncertain significance	criteria provided, single submitter
3892565	NM_001042750.2(STAG2):c.3058G>T (p.Val1020Phe)	STAG2	Uncertain significance	criteria provided, single submitter
367872	NM_002351.5(SH2D1A):c.48C>T (p.Gly16=)	SH2D1A	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1077153	NM_001042750.2(STAG2):c.1535-3del	STAG2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1237421	NM_001042750.2(STAG2):c.1417-39A>C	STAG2	Benign	criteria provided, multiple submitters, no conflicts
1612997	NM_001042750.2(STAG2):c.1101T>C (p.Phe367=)	STAG2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1664876	NM_001042750.2(STAG2):c.45-11T>C	STAG2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
3780667	NM_001042750.2(STAG2):c.1535-6_1535-3dup	STAG2	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SH2D1A	Orphanet:538931	X-linked lymphoproliferative disease due to SAP deficiency
STAG2	Orphanet:220386	Semilobar holoprosencephaly
STAG2	Orphanet:521258	Xq25 microduplication syndrome
STAG2	Orphanet:93925	Alobar holoprosencephaly

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
SH2D1A	HGNC:10820	ENSG00000183918	O60880	SH2 domain-containing protein 1A	clinvar
STAG2	HGNC:11355	ENSG00000101972	Q8N3U4	Cohesin subunit SA-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SH2D1A	SH2 domain-containing protein 1A	Cytoplasmic adapter regulating receptors of the signaling lymphocytic activation molecule (SLAM) family such as SLAMF1, CD244, LY9, CD84, SLAMF6 and SLAMF7.
STAG2	Cohesin subunit SA-2	Component of cohesin complex, a complex required for the cohesion of sister chromatids after DNA replication.

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)
SH2D1A	Scaffold/PPI	no		SH2, SH2_prot_1A, SH2D1A_SH2
STAG2	Other/Unknown	no		STAG, ARM-type_fold, SCD

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
granulocyte	1
lymph node	1
thymus	1
calcaneal tendon	1
mucosa of paranasal sinus	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SH2D1A	170	broad	marker	thymus, lymph node, granulocyte
STAG2	299	ubiquitous	marker	mucosa of paranasal sinus, calcaneal tendon, sural nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
STAG2	2,945
SH2D1A	1,548

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
STAG2	Q8N3U4	9
SH2D1A	O60880	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 27. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Mitotic Telophase/Cytokinesis	1	713.8×	0.017	STAG2
Cohesin Loading onto Chromatin	1	571.0×	0.017	STAG2
Establishment of Sister Chromatid Cohesion	1	519.1×	0.017	STAG2
Meiosis	1	142.8×	0.038	STAG2
Reproduction	1	95.2×	0.038	STAG2
S Phase	1	90.6×	0.038	STAG2
SUMO E3 ligases SUMOylate target proteins	1	89.2×	0.038	STAG2
SUMOylation	1	81.6×	0.038	STAG2
SUMOylation of DNA damage response and repair proteins	1	73.2×	0.038	STAG2
Meiotic synapsis	1	70.5×	0.038	STAG2
ESR-mediated signaling	1	64.2×	0.038	STAG2
Signaling by Nuclear Receptors	1	51.0×	0.039	STAG2
Mitotic Metaphase and Anaphase	1	48.4×	0.039	STAG2
Mitotic Anaphase	1	48.4×	0.039	STAG2
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	1	43.6×	0.039	SH2D1A
Resolution of Sister Chromatid Cohesion	1	43.3×	0.039	STAG2
Estrogen-dependent gene expression	1	37.8×	0.042	STAG2
Mitotic Prometaphase	1	34.6×	0.043	STAG2
M Phase	1	33.0×	0.043	STAG2
Separation of Sister Chromatids	1	30.4×	0.044	STAG2
Cell Cycle, Mitotic	1	24.1×	0.053	STAG2
Cell Cycle	1	18.0×	0.067	STAG2
Adaptive Immune System	1	14.9×	0.077	SH2D1A
Post-translational protein modification	1	9.6×	0.114	STAG2
Immune System	1	6.5×	0.160	SH2D1A
Metabolism of proteins	1	6.2×	0.161	STAG2
Signal Transduction	1	5.1×	0.187	STAG2

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
establishment of mitotic sister chromatid cohesion	1	1203.7×	0.010	STAG2
sister chromatid cohesion	1	383.0×	0.010	STAG2
natural killer cell activation	1	290.6×	0.010	SH2D1A
positive regulation of natural killer cell mediated cytotoxicity	1	280.9×	0.010	SH2D1A
regulation of immune response	1	247.8×	0.010	SH2D1A
natural killer cell mediated cytotoxicity	1	216.1×	0.010	SH2D1A
negative regulation of T cell receptor signaling pathway	1	183.2×	0.010	SH2D1A
mitotic spindle assembly	1	172.0×	0.010	STAG2
cellular defense response	1	159.0×	0.010	SH2D1A
humoral immune response	1	140.4×	0.010	SH2D1A
meiotic cell cycle	1	122.1×	0.010	STAG2
adaptive immune response	1	42.1×	0.028	SH2D1A
cell-cell signaling	1	34.8×	0.031	SH2D1A
cell division	1	23.1×	0.043	STAG2

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
SH2D1A	0	0
STAG2	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
SH2D1A	5	Binding:5

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	SH2D1A, STAG2

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)
SH2D1A	5	—
STAG2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.