Baller-Gerold syndrome

Summary

Baller-Gerold syndrome (MONDO:0009039) is a disease caused by RECQL4 (GenCC Definitive), with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: RECQL4 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 4,847
• Phenotypes (HPO): 43

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		40	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

43 HPO clinical features (Orphanet curated; top 43 by frequency):

HPO ID	Term	Frequency
HP:0009380	Finger aplasia	Very frequent (80-99%)
HP:0000239	Large fontanelles	Very frequent (80-99%)
HP:0000244	Brachyturricephaly	Very frequent (80-99%)
HP:0000248	Brachycephaly	Very frequent (80-99%)
HP:0000520	Proptosis	Very frequent (80-99%)
HP:0001510	Growth delay	Very frequent (80-99%)
HP:0001531	Failure to thrive in infancy	Very frequent (80-99%)
HP:0002007	Frontal bossing	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0006501	Aplasia/Hypoplasia of the radius	Very frequent (80-99%)
HP:0009601	Aplasia/Hypoplasia of the thumb	Very frequent (80-99%)
HP:0000160	Narrow mouth	Frequent (30-79%)
HP:0000218	High palate	Frequent (30-79%)
HP:0001191	Abnormal carpal morphology	Frequent (30-79%)
HP:0001511	Intrauterine growth retardation	Frequent (30-79%)
HP:0001545	Anteriorly placed anus	Frequent (30-79%)
HP:0002024	Malabsorption	Frequent (30-79%)
HP:0003196	Short nose	Frequent (30-79%)
HP:0005916	Abnormal metacarpal morphology	Frequent (30-79%)
HP:0006487	Bowing of the long bones	Frequent (30-79%)
HP:0006498	Aplasia/Hypoplasia of the patella	Frequent (30-79%)
HP:0000069	Abnormality of the ureter	Occasional (5-29%)
HP:0000076	Vesicoureteral reflux	Occasional (5-29%)
HP:0000126	Hydronephrosis	Occasional (5-29%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0000275	Narrow face	Occasional (5-29%)
HP:0000286	Epicanthus	Occasional (5-29%)
HP:0000316	Hypertelorism	Occasional (5-29%)
HP:0000337	Broad forehead	Occasional (5-29%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0000405	Conductive hearing impairment	Occasional (5-29%)
HP:0000426	Prominent nasal bridge	Occasional (5-29%)
HP:0000446	Narrow nasal bridge	Occasional (5-29%)
HP:0000601	Hypotelorism	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0001029	Poikiloderma	Occasional (5-29%)
HP:0001671	Abnormal cardiac septum morphology	Occasional (5-29%)
HP:0002023	Anal atresia	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002665	Lymphoma	Occasional (5-29%)
HP:0002669	Osteosarcoma	Occasional (5-29%)
HP:0100542	Abnormal localization of kidney	Occasional (5-29%)
HP:0100589	Urogenital fistula	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Baller-Gerold syndrome
Mondo ID	MONDO:0009039
MeSH	C536788
OMIM	218600
Orphanet	1225
DOID	DOID:0050654
ICD-11	1650688177
SNOMED CT	77608001
UMLS	C0265308
MedGen	120532
GARD	0001602
NORD	834
Is cancer (heuristic)	no

Also known as: Baller-Gerold syndrome · BGS

Data availability: 4,847 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › syndromic craniosynostosis › Baller-Gerold syndrome

Related subtypes (39): Crouzon syndrome, Beare-Stevenson cutis gyrata syndrome, Shprintzen-Goldberg syndrome, acrocephalopolydactyly, Antley-Bixler syndrome, C syndrome, cranioectodermal dysplasia, cardiocranial syndrome, Pfeiffer type, craniosynostosis-fibular aplasia syndrome, craniotelencephalic dysplasia, Summitt syndrome, X-linked intellectual disability-plagiocephaly syndrome, Lowry-MacLean syndrome, pseudoaminopterin syndrome, craniosynostosis 4, holoprosencephaly-craniosynostosis syndrome, Hunter-McAlpine craniosynostosis, Curry-Jones syndrome, craniomicromelic syndrome, Muenke syndrome, craniosynostosis-anal anomalies-porokeratosis syndrome, craniosynostosis 2, cloverleaf skull-multiple congenital anomalies syndrome, craniosynostosis-intracranial calcifications syndrome, Crouzon syndrome-acanthosis nigricans syndrome, craniosynostosis and dental anomalies, lethal occipital encephalocele-skeletal dysplasia syndrome, TCF12-related craniosynostosis, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, cloverleaf skull-asphyxiating thoracic dysplasia syndrome, craniosynostosis, Philadelphia type, craniosynostosis-cataract syndrome, familial scaphocephaly syndrome, craniosynostosis-hydrocephalus-Arnold-Chiari malformation type I-radioulnar synostosis syndrome, osteosclerosis-developmental delay-craniosynostosis syndrome, craniosynostosis, Herrmann-Opitz type, trigonocephaly-broad thumbs syndrome, acrocephalosyndactyly, Weiss-Kruszka 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

600 retrieved; paginated sample, class counts are floors:

308 uncertain significance, 237 likely benign, 34 pathogenic, 15 conflicting classifications of pathogenicity, 4 likely pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069588	NM_004260.4(RECQL4):c.37_38delinsTA (p.Ala13Ter)	LOC130001411	Pathogenic	criteria provided, single submitter
1070089	NM_004260.4(RECQL4):c.126C>G (p.Tyr42Ter)	LOC130001411	Pathogenic	criteria provided, single submitter
1073335	NM_004260.4(RECQL4):c.42G>A (p.Trp14Ter)	LOC130001411	Pathogenic	criteria provided, single submitter
1029808	NM_004260.4(RECQL4):c.615dup (p.Lys206fs)	RECQL4	Pathogenic	criteria provided, single submitter
1065954	NM_004260.4(RECQL4):c.3236G>T (p.Ser1079Ile)	RECQL4	Pathogenic	criteria provided, single submitter
1068625	NM_004260.4(RECQL4):c.652_653del (p.Gln218fs)	RECQL4	Pathogenic	criteria provided, single submitter
1069365	NM_004260.4(RECQL4):c.3284_3287dup (p.Ser1097fs)	RECQL4	Pathogenic	criteria provided, single submitter
1069662	NM_004260.4(RECQL4):c.897del (p.Glu301fs)	RECQL4	Pathogenic	criteria provided, single submitter
1069990	NM_004260.4(RECQL4):c.3331G>T (p.Glu1111Ter)	RECQL4	Pathogenic	criteria provided, single submitter
1070028	NM_004260.4(RECQL4):c.1089C>A (p.Tyr363Ter)	RECQL4	Pathogenic	criteria provided, multiple submitters, no conflicts
1070092	NM_004260.4(RECQL4):c.1561del (p.Arg521fs)	RECQL4	Pathogenic	criteria provided, single submitter
1070117	NM_004260.4(RECQL4):c.2631C>G (p.Tyr877Ter)	RECQL4	Pathogenic	criteria provided, single submitter
1070337	NM_004260.4(RECQL4):c.2083A>T (p.Lys695Ter)	RECQL4	Pathogenic	criteria provided, single submitter
1070358	NM_004260.4(RECQL4):c.1162G>T (p.Glu388Ter)	RECQL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070691	NM_004260.4(RECQL4):c.988_1004del (p.Ala330fs)	RECQL4	Pathogenic	criteria provided, single submitter
1070864	NC_000008.10:g.(?145738945)(145743168_?)del	RECQL4	Pathogenic	criteria provided, single submitter
1070865	NC_000008.10:g.(?_145737562)_145739175del	RECQL4	Pathogenic	criteria provided, single submitter
1071000	NM_004260.4(RECQL4):c.3163del (p.Leu1055fs)	RECQL4	Pathogenic	criteria provided, single submitter
1071942	NM_004260.4(RECQL4):c.2096del (p.Asn699fs)	RECQL4	Pathogenic	criteria provided, single submitter
1072153	NM_004260.4(RECQL4):c.670G>T (p.Glu224Ter)	RECQL4	Pathogenic	criteria provided, single submitter
1072762	NM_004260.4(RECQL4):c.2092C>T (p.Gln698Ter)	RECQL4	Pathogenic	criteria provided, single submitter
1072952	NM_004260.4(RECQL4):c.2026del (p.Leu676fs)	RECQL4	Pathogenic	criteria provided, single submitter
1073755	NM_004260.4(RECQL4):c.1078C>T (p.Gln360Ter)	RECQL4	Pathogenic	criteria provided, multiple submitters, no conflicts
1073779	NM_004260.4(RECQL4):c.3321C>G (p.Tyr1107Ter)	RECQL4	Pathogenic	criteria provided, single submitter
1073983	NM_004260.4(RECQL4):c.2305del (p.Val769fs)	RECQL4	Pathogenic	criteria provided, single submitter
1074685	NM_004260.4(RECQL4):c.1390+2T>C	RECQL4	Pathogenic	criteria provided, single submitter
1074968	NM_004260.4(RECQL4):c.2650del (p.Gln884fs)	RECQL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075387	NM_004260.4(RECQL4):c.3223C>T (p.Gln1075Ter)	RECQL4	Pathogenic	criteria provided, single submitter
1075388	NM_004260.4(RECQL4):c.55C>T (p.Arg19Ter)	RECQL4	Pathogenic	criteria provided, single submitter
1075795	NM_004260.4(RECQL4):c.3035G>A (p.Trp1012Ter)	RECQL4	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 3 · 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
RECQL4	Definitive	Autosomal recessive	Baller-Gerold syndrome	15

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RECQL4	Orphanet:1225	Baller-Gerold syndrome
RECQL4	Orphanet:221016	Rothmund-Thomson syndrome type 2
RECQL4	Orphanet:3021	RAPADILINO syndrome

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
RECQL4	HGNC:9949	ENSG00000160957	O94761	ATP-dependent DNA helicase Q4	gencc,clinvar
LRRC14	HGNC:20419	ENSG00000160959	Q15048	Leucine-rich repeat-containing protein 14	clinvar
ARHGAP39	HGNC:29351	ENSG00000147799	Q9C0H5	Rho GTPase-activating protein 39	clinvar
GPT	HGNC:4552	ENSG00000167701	P24298	Alanine aminotransferase 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RECQL4	ATP-dependent DNA helicase Q4	An ATP-dependent DNA helicase which unwinds dsDNA with a 3’-overhang in a 3’-5’ direction.
LRRC14	Leucine-rich repeat-containing protein 14	Negatively regulates Toll-like receptor-mediated NF-kappa-B signaling by disrupting IKK core complex formation through interaction with IKBKB.
GPT	Alanine aminotransferase 1	Catalyzes the reversible transamination between alanine and 2-oxoglutarate to form pyruvate and glutamate.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.5

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
Enzyme (other)	2	6.0×	0.112
Scaffold/PPI	1	4.3×	0.318
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RECQL4	Enzyme (other)	yes	3.6.4.12	Helicase_C-like, DNA_helicase_ATP-dep_RecQ, DEAD/DEAH_box_helicase_dom
LRRC14	Other/Unknown	no		Leu-rich_rpt, LRR_dom_sf, LRRC14/PRAME
ARHGAP39	Scaffold/PPI	no		RhoGAP_dom, MyTH4_dom, WW_dom
GPT	Enzyme (other)	yes	2.6.1.2	Aminotransferase_I/II_large, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase_small

Expression context

Cohort genes with no expression data: 0.

3 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
mucosa of transverse colon	3
lower esophagus mucosa	2
ventricular zone	1
right lobe of thyroid gland	1
oviduct epithelium	1
right uterine tube	1
sural nerve	1
apex of heart	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RECQL4	212	ubiquitous	yes	lower esophagus mucosa, ventricular zone, mucosa of transverse colon
LRRC14	238	ubiquitous	marker	lower esophagus mucosa, mucosa of transverse colon, right lobe of thyroid gland
ARHGAP39	191	ubiquitous	marker	sural nerve, oviduct epithelium, right uterine tube
GPT	183	broad	marker	right lobe of liver, mucosa of transverse colon, apex of heart

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RECQL4	6,330
GPT	4,344
LRRC14	1,486
ARHGAP39	1,449

Intra-cohort edges

A	B	Sources
ARHGAP39	LRRC14	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RECQL4	O94761	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GPT	P24298	95.32
LRRC14	Q15048	87.76
ARHGAP39	Q9C0H5	59.42

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 40. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Alanine metabolism	1	1903.3×	0.021	GPT
Inactivation of CDC42 and RAC1	1	475.8×	0.033	ARHGAP39
Regulation of NF-kappa B signaling	1	211.5×	0.033	LRRC14
Pyruvate metabolism	1	135.9×	0.033	GPT
TAK1-dependent IKK and NF-kappa-B activation	1	100.2×	0.033	LRRC14
Interleukin-1 family signaling	1	90.6×	0.033	LRRC14
RHOF GTPase cycle	1	86.5×	0.033	ARHGAP39
Toll Like Receptor 10 (TLR10) Cascade	1	71.8×	0.033	LRRC14
Toll Like Receptor 5 (TLR5) Cascade	1	71.8×	0.033	LRRC14
RHOD GTPase cycle	1	68.0×	0.033	ARHGAP39
MyD88 cascade initiated on plasma membrane	1	68.0×	0.033	LRRC14
Toll Like Receptor 3 (TLR3) Cascade	1	64.5×	0.033	LRRC14
TRIF (TICAM1)-mediated TLR4 signaling	1	63.4×	0.033	LRRC14
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	1	63.4×	0.033	LRRC14
MyD88 dependent cascade initiated on endosome	1	63.4×	0.033	LRRC14
MyD88-independent TLR4 cascade	1	61.4×	0.033	LRRC14
Toll Like Receptor 7/8 (TLR7/8) Cascade	1	61.4×	0.033	LRRC14
Toll Like Receptor 9 (TLR9) Cascade	1	58.6×	0.033	LRRC14
Toll Like Receptor TLR6:TLR2 Cascade	1	58.6×	0.033	LRRC14
Toll Like Receptor 2 (TLR2) Cascade	1	57.7×	0.033	LRRC14
Toll Like Receptor TLR1:TLR2 Cascade	1	56.0×	0.033	LRRC14
RHOB GTPase cycle	1	51.4×	0.033	ARHGAP39
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	1	50.8×	0.033	LRRC14
RHOG GTPase cycle	1	49.4×	0.033	ARHGAP39
RHOC GTPase cycle	1	48.8×	0.033	ARHGAP39
Toll Like Receptor 4 (TLR4) Cascade	1	43.8×	0.033	LRRC14
RAC2 GTPase cycle	1	42.3×	0.033	ARHGAP39
Toll-like Receptor Cascades	1	41.4×	0.033	LRRC14
Interleukin-1 signaling	1	41.4×	0.033	LRRC14
RAC3 GTPase cycle	1	39.6×	0.033	ARHGAP39

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
L-alanine catabolic process	1	1053.2×	0.008	GPT
postsynapse organization	1	601.9×	0.008	ARHGAP39
telomeric D-loop disassembly	1	468.1×	0.008	RECQL4
negative regulation of toll-like receptor signaling pathway	1	210.7×	0.013	LRRC14
obsolete negative regulation of NF-kappaB transcription factor activity	1	89.6×	0.024	LRRC14
telomere maintenance	1	66.9×	0.027	RECQL4
DNA replication	1	41.3×	0.034	RECQL4
double-strand break repair via homologous recombination	1	39.0×	0.034	RECQL4
regulation of small GTPase mediated signal transduction	1	36.0×	0.034	ARHGAP39
DNA repair	1	16.0×	0.067	RECQL4
signal transduction	1	4.0×	0.227	ARHGAP39

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
RECQL4	0	0
LRRC14	0	0
ARHGAP39	0	0
GPT	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
GPT	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RECQL4	3.6.4.12	DNA helicase
GPT	2.6.1.2, 2.6.1.4	alanine transaminase, glycine transaminase

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	1	RECQL4
D	Druggable family + AlphaFold only, no drug	1	GPT
E	Difficult family or no structure, no drug	2	LRRC14, ARHGAP39

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)
RECQL4	0	—
LRRC14	0	—
ARHGAP39	0	—
GPT	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.