Laterality defects, autosomal dominant

Summary

Laterality defects, autosomal dominant (MONDO:0010991) is a disease with 10 cohort genes.

At a glance

• Cohort genes: 10
• ClinVar variants: 12

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	laterality defects, autosomal dominant
Mondo ID	MONDO:0010991
MeSH	C563391
OMIM	601086
UMLS	C1832813
MedGen	322042
GARD	0003198
Is cancer (heuristic)	no

Also known as: laterality defects dominant · laterality defects, autosomal dominant

Data availability: 12 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › visceral heterotaxy › laterality defects, autosomal dominant

Related subtypes (18): right atrial isomerism, situs inversus, heterotaxy, visceral, 1, X-linked, heterotaxy, visceral, 2, autosomal, heterotaxy, visceral, 3, autosomal, heterotaxy, visceral, 4, autosomal, heterotaxy, visceral, 6, autosomal, heterotaxy, visceral, 7, autosomal, heterotaxy, visceral, 8, autosomal, dextrocardia, levocardia, heterotaxy, visceral, 9, autosomal, with male infertility, heterotaxy, visceral, 10, autosomal, with male infertility, heterotaxy, visceral, 11, autosomal, with male infertility, heterotaxy, visceral, 5, autosomal, heterotaxy, visceral, 12, autosomal, heterotaxy, visceral, 13, autosomal, heterotaxy, visceral, 14, autosomal

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

12 retrieved; paginated sample, class counts are floors:

9 uncertain significance, 2 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1453371	NM_001277115.2(DNAH11):c.2406G>A (p.Trp802Ter)	DNAH11	Pathogenic	criteria provided, single submitter
3233431	NM_001277115.2(DNAH11):c.12058_12059del (p.Met4020fs)	DNAH11	Likely pathogenic	no assertion criteria provided
3233432	NM_001277115.2(DNAH11):c.10215_10218del (p.Lys3405fs)	DNAH11	Likely pathogenic	no assertion criteria provided
2591933	NM_175859.3(CTPS2):c.757G>A (p.Val253Ile)	CTPS2	Uncertain significance	criteria provided, single submitter
3233433	NM_020877.5(DNAH2):c.11309C>T (p.Pro3770Leu)	DNAH2	Uncertain significance	no assertion criteria provided
3233435	NM_001110556.2(FLNA):c.7258G>A (p.Val2420Ile)	FLNA	Uncertain significance	no assertion criteria provided
3233436	NM_194463.2(RNF128):c.514G>A (p.Gly172Ser)	RNF128	Uncertain significance	no assertion criteria provided
3233437	NM_194463.2(RNF128):c.1243G>A (p.Glu415Lys)	RNF128	Uncertain significance	no assertion criteria provided
3018256	NM_031892.3(SH3KBP1):c.1265C>T (p.Pro422Leu)	SH3KBP1	Uncertain significance	criteria provided, single submitter
3233430	NM_001142286.2(SMC6):c.121-1G>T	SMC6	Uncertain significance	no assertion criteria provided
3173120	NM_138780.3(SYTL5):c.1534A>T (p.Ile512Phe)	SYTL5	Uncertain significance	criteria provided, single submitter
3233434	NM_001346022.3(USP45):c.2222C>T (p.Ser741Leu)	USP45	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 15 · 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
ANKS3	Limited	Autosomal recessive	laterality defects, autosomal dominant	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ANKS3	Orphanet:101063	Situs inversus totalis
SH3KBP1	Orphanet:696945	X-linked common variable immunodeficiency phenotype due to SH3KBP1 deficiency
USP45	Orphanet:65	Leber congenital amaurosis
DNAH11	Orphanet:244	Primary ciliary dyskinesia
FLNA	Orphanet:1826	Frontometaphyseal dysplasia
FLNA	Orphanet:2301	Congenital short bowel syndrome
FLNA	Orphanet:2484	Melnick-Needles syndrome
FLNA	Orphanet:482606	X-linked keloid scarring-reduced joint mobility-increased optic cup-to-disc ratio syndrome
FLNA	Orphanet:555877	FLNA-related X-linked myxomatous valvular dysplasia
FLNA	Orphanet:75497	X-linked Ehlers-Danlos syndrome
FLNA	Orphanet:88630	Terminal osseous dysplasia-pigmentary defects syndrome
FLNA	Orphanet:90650	Otopalatodigital syndrome type 1
FLNA	Orphanet:90652	Otopalatodigital syndrome type 2
FLNA	Orphanet:98892	Periventricular nodular heterotopia
FLNA	Orphanet:99811	Neuronal intestinal pseudoobstruction

Cohort genes → proteins

10 cohort genes, 10 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	10

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ANKS3	HGNC:29422	ENSG00000168096	Q6ZW76	Ankyrin repeat and SAM domain-containing protein 3	gencc
SH3KBP1	HGNC:13867	ENSG00000147010	Q96B97	SH3 domain-containing kinase-binding protein 1	clinvar
SYTL5	HGNC:15589	ENSG00000147041	Q8TDW5	Synaptotagmin-like protein 5	clinvar
USP45	HGNC:20080	ENSG00000123552	Q70EL2	Ubiquitin carboxyl-terminal hydrolase 45	clinvar
SMC6	HGNC:20466	ENSG00000163029	Q96SB8	Structural maintenance of chromosomes protein 6	clinvar
RNF128	HGNC:21153	ENSG00000133135	Q8TEB7	E3 ubiquitin-protein ligase RNF128	clinvar
CTPS2	HGNC:2520	ENSG00000047230	Q9NRF8	CTP synthase 2	clinvar
DNAH11	HGNC:2942	ENSG00000105877	Q96DT5	Dynein axonemal heavy chain 11	clinvar
DNAH2	HGNC:2948	ENSG00000183914	Q9P225	Dynein axonemal heavy chain 2	clinvar
FLNA	HGNC:3754	ENSG00000196924	P21333	Filamin-A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ANKS3	Ankyrin repeat and SAM domain-containing protein 3	May be involved in vasopressin signaling in the kidney.
SH3KBP1	SH3 domain-containing kinase-binding protein 1	Adapter protein involved in regulating diverse signal transduction pathways.
SYTL5	Synaptotagmin-like protein 5	May act as Rab effector protein and play a role in vesicle trafficking.
USP45	Ubiquitin carboxyl-terminal hydrolase 45	Catalyzes the deubiquitination of SPDL1.
SMC6	Structural maintenance of chromosomes protein 6	Core component of the SMC5-SMC6 complex, a complex involved in DNA double-strand breaks by homologous recombination.
RNF128	E3 ubiquitin-protein ligase RNF128	E3 ubiquitin-protein ligase that catalyzes ‘Lys-27’, ‘Lys-48’- or ‘Lys-63’-linked polyubiquitin chains formation and plays a role in different biological processes such as modulation of immune response, cytoskeletal dynamics or protein hom…
CTPS2	CTP synthase 2	CTP synthase involved in the de novo synthesis of CTP, a precursor of DNA, RNA and phospholipids.
DNAH11	Dynein axonemal heavy chain 11	Force generating protein required for cilia beating in respiratory epithelia.
DNAH2	Dynein axonemal heavy chain 2	As part of the axonemal inner dynein arm complex plays a central role in ciliary beat.
FLNA	Filamin-A	Promotes orthogonal branching of actin filaments and links actin filaments to membrane glycoproteins.

Protein-family classification

Druggable: 3 · Difficult: 4 · Unknown: 3 · Druggable fraction: 0.3

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
Protease	1	3.7×	0.519
Scaffold/PPI	2	3.5×	0.519
Antibody/Immunoglobulin	1	2.9×	0.519
Transcription factor	2	1.6×	0.519
Enzyme (other)	1	1.2×	0.698
Other/Unknown	3	0.5×	0.976

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ANKS3	Scaffold/PPI	no		SAM, Ankyrin_rpt, SAM/pointed_sf
SH3KBP1	Scaffold/PPI	no		SH3_domain, CIN85_SH3_1, CIN85_SH3_2
SYTL5	Transcription factor	no		C2_dom, Rab_BD, Znf_FYVE_PHD
USP45	Protease	yes		Peptidase_C19_UCH, Znf_UBP, Znf_RING/FYVE/PHD
SMC6	Other/Unknown	no		RecF/RecN/SMC_N, P-loop_NTPase
RNF128	Transcription factor	no		Znf_RING, PA_domain, Znf_RING/FYVE/PHD
CTPS2	Enzyme (other)	yes	6.3.4.2	CTP_synthase, CTP_synthase_N, GATASE
DNAH11	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail
DNAH2	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail
FLNA	Antibody/Immunoglobulin	yes		Filamin/ABP280_rpt, Actinin_actin-bd_CS, CH_dom

Expression context

Cohort genes with no expression data: 0.

9 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)	10
unknown	0

Top tissues across cohort

Tissue	Cohort genes
secondary oocyte	3
ileal mucosa	2
jejunal mucosa	2
bronchial epithelial cell	2
bronchus	2
right uterine tube	2
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
left ventricle myocardium	1
palpebral conjunctiva	1
pancreatic ductal cell	1
calcaneal tendon	1
epithelial cell of pancreas	1
male germ cell	1
sperm	1
nephron tubule	1
parotid gland	1
body of pancreas	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ANKS3	195	ubiquitous	yes	cerebellar hemisphere, right hemisphere of cerebellum, cerebellar cortex
SH3KBP1	254	ubiquitous	marker	secondary oocyte, left ventricle myocardium, ileal mucosa
SYTL5	176	tissue_specific	marker	pancreatic ductal cell, ileal mucosa, palpebral conjunctiva
USP45	225	ubiquitous	marker	calcaneal tendon, secondary oocyte, epithelial cell of pancreas
SMC6	269	ubiquitous	marker	sperm, male germ cell, secondary oocyte
RNF128	245	broad	marker	jejunal mucosa, parotid gland, nephron tubule
CTPS2	246	ubiquitous	marker	jejunal mucosa, ventricular zone, body of pancreas
DNAH11	163	broad	marker	right uterine tube, bronchial epithelial cell, bronchus
DNAH2	139	tissue_specific	marker	bronchial epithelial cell, right uterine tube, bronchus
FLNA	285	ubiquitous	marker	right coronary artery, popliteal artery, tibial artery

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FLNA	5,321
CTPS2	3,397
SMC6	2,956
SH3KBP1	2,825
DNAH11	1,666
DNAH2	1,556
ANKS3	1,410
RNF128	1,239
USP45	951
SYTL5	657

Structural data

PDB: 7 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FLNA	P21333	26
CTPS2	Q9NRF8	8
SH3KBP1	Q96B97	7
SMC6	Q96SB8	4
ANKS3	Q6ZW76	2
RNF128	Q8TEB7	1
DNAH2	Q9P225	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
USP45	Q70EL2	66.28
SYTL5	Q8TDW5	65.97
DNAH11	Q96DT5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 41. Enrichment computed across 10 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Reelin signalling pathway	1	317.2×	0.051	SH3KBP1
OAS antiviral response	1	211.5×	0.051	FLNA
Listeria monocytogenes entry into host cells	1	173.0×	0.051	SH3KBP1
GP1b-IX-V activation signalling	1	158.6×	0.051	FLNA
InlB-mediated entry of Listeria monocytogenes into host cell	1	126.9×	0.051	SH3KBP1
Cell-extracellular matrix interactions	1	112.0×	0.051	FLNA
RHO GTPases activate PAKs	1	90.6×	0.051	FLNA
Negative regulation of MET activity	1	86.5×	0.051	SH3KBP1
Interconversion of nucleotide di- and triphosphates	1	59.5×	0.051	CTPS2
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	1	59.5×	0.051	SH3KBP1
EGFR downregulation	1	57.7×	0.051	SH3KBP1
Signaling by the B Cell Receptor (BCR)	1	57.7×	0.051	SH3KBP1
Bacterial Infection Pathways	1	56.0×	0.051	SH3KBP1
Signaling by EGFR	1	54.4×	0.051	SH3KBP1
Signaling by MET	1	52.9×	0.051	SH3KBP1
Ovarian tumor domain proteases	1	46.4×	0.055	RNF128
Formation of Incision Complex in GG-NER	1	42.3×	0.056	USP45
SUMO E3 ligases SUMOylate target proteins	1	29.7×	0.074	SMC6
SUMOylation	1	27.2×	0.074	SMC6
Post-translational protein modification	2	6.4×	0.074	SMC6, RNF128
SUMOylation of DNA damage response and repair proteins	1	24.4×	0.079	SMC6
Deubiquitination	1	20.7×	0.088	RNF128
Potential therapeutics for SARS	1	19.0×	0.092	SH3KBP1
Cargo recognition for clathrin-mediated endocytosis	1	17.5×	0.096	SH3KBP1
Platelet degranulation	1	14.6×	0.108	FLNA
Clathrin-mediated endocytosis	1	14.2×	0.108	SH3KBP1
Metabolism of proteins	2	4.1×	0.119	SMC6, RNF128
SARS-CoV Infections	1	9.2×	0.151	SH3KBP1
Ub-specific processing proteases	1	8.8×	0.151	RNF128
Signaling by Receptor Tyrosine Kinases	1	8.6×	0.151	SH3KBP1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 9 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cilium movement involved in cell motility	2	149.8×	0.006	DNAH11, DNAH2
regulation of membrane repolarization during atrial cardiac muscle cell action potential	1	1872.4×	0.013	FLNA
regulation of membrane repolarization during cardiac muscle cell action potential	1	1872.4×	0.013	FLNA
determination of left/right asymmetry in nervous system	1	936.2×	0.013	DNAH11
‘de novo’ CTP biosynthetic process	1	936.2×	0.013	CTPS2
global genome nucleotide-excision repair	1	936.2×	0.013	USP45
positive regulation of protein catabolic process in the vacuole	1	936.2×	0.013	RNF128
pyrimidine nucleobase biosynthetic process	1	624.1×	0.015	CTPS2
tubulin deacetylation	1	624.1×	0.015	FLNA
pyrimidine nucleotide metabolic process	1	468.1×	0.016	CTPS2
formation of radial glial scaffolds	1	468.1×	0.016	FLNA
adenylate cyclase-inhibiting dopamine receptor signaling pathway	1	374.5×	0.016	FLNA
establishment of Sertoli cell barrier	1	374.5×	0.016	FLNA
protein localization to motile cilium	1	374.5×	0.016	DNAH11
protein localization to bicellular tight junction	1	312.1×	0.018	FLNA
negative regulation of transcription by RNA polymerase I	1	267.5×	0.019	FLNA
regulation of cilium beat frequency	1	234.1×	0.019	DNAH11
blood coagulation, intrinsic pathway	1	234.1×	0.019	FLNA
positive regulation of B cell activation	1	234.1×	0.019	SH3KBP1
CTP biosynthetic process	1	187.2×	0.020	CTPS2
telomere maintenance via recombination	1	170.2×	0.020	SMC6
host-mediated suppression of viral genome replication	1	170.2×	0.020	SMC6
cilium-dependent cell motility	1	156.0×	0.020	DNAH2
positive regulation of platelet activation	1	144.0×	0.020	FLNA
positive regulation of chromosome segregation	1	144.0×	0.020	SMC6
epithelial cilium movement involved in determination of left/right asymmetry	1	144.0×	0.020	DNAH11
positive regulation of integrin-mediated signaling pathway	1	144.0×	0.020	FLNA
positive regulation of actin filament bundle assembly	1	133.8×	0.020	FLNA
actin crosslink formation	1	133.8×	0.020	FLNA
cardiac septum morphogenesis	1	133.8×	0.020	DNAH11

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 9

Druggability breadth: 3 of 10 evidence-associated genes (30%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FLNA	1	2
ANKS3	0	0
SH3KBP1	0	0
SYTL5	0	0
USP45	0	0
SMC6	0	0
RNF128	0	0
CTPS2	0	0
DNAH11	0	0
DNAH2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	FLNA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
FLNA	7	Binding:7
USP45	3	Binding:3
CTPS2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CTPS2	6.3.4.2	CTP synthase (glutamine hydrolysing)

Pharmacogenomics

Cohort genes with a PharmGKB record: 10; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 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.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	FLNA

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	1	FLNA
C	Druggable family + PDB, no drug	1	CTPS2
D	Druggable family + AlphaFold only, no drug	1	USP45
E	Difficult family or no structure, no drug	7	ANKS3, SH3KBP1, SYTL5, SMC6, RNF128, DNAH11, DNAH2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ANKS3	0	—
SH3KBP1	0	—
SYTL5	0	—
USP45	3	—
SMC6	0	—
RNF128	0	—
CTPS2	1	—
DNAH11	0	—
DNAH2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.