Rajab interstitial lung disease with brain calcifications 1

Summary

Rajab interstitial lung disease with brain calcifications 1 (MONDO:0100215) is a disease caused by FARSB (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: FARSB (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 8

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		8	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Rajab interstitial lung disease with brain calcifications 1
Mondo ID	MONDO:0100215
OMIM	613658, 618007
Orphanet	178506
SNOMED CT	720576001
UMLS	C5436276
MedGen	1750003
GARD	0018297
Is cancer (heuristic)	no

Also known as: brain calcification, Rajab type · developmental delay, small stature, microcephaly, and brain calcifications · NEDBLLA · neurodevelopmental disorder with brain, liver, and lung abnormalities

Data availability: 8 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › Rajab interstitial lung disease with brain calcifications 1

Related subtypes (218): immunodeficiency-centromeric instability-facial anomalies syndrome, hypercalcemia, infantile, Ochoa syndrome, autosomal recessive Ehlers-Danlos syndrome, vascular type, hydrolethalus syndrome, 3-M syndrome, isolated hyperchlorhidrosis, dacryocystitis-osteopoikilosis syndrome, Hutchinson-Gilford progeria syndrome, achalasia microcephaly syndrome, acrorenal syndrome, autosomal recessive, beta-ketothiolase deficiency, autosomal recessive Alport syndrome, Alstrom syndrome, microphthalmia with limb anomalies, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, Behr syndrome, bifid nose, autosomal recessive, Bloom syndrome, Bowen-Conradi syndrome, camptodactyly with fibrous tissue hyperplasia and skeletal dysplasia, heart defects-limb shortening syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, COFS syndrome, craniometaphyseal dysplasia, autosomal recessive, Fraser syndrome, cystic fibrosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, persistent hyperplastic primary vitreous, autosomal recessive, Donnai-Barrow syndrome, Schöpf-Schulz-Passarge syndrome, cleft lip/palate-ectodermal dysplasia syndrome, Ellis-van Creveld syndrome, Wolcott-Rallison syndrome, autosomal recessive faciodigitogenital syndrome, acromesomelic dysplasia 2B, brittle cornea syndrome, triple-A syndrome, autosomal recessive humeroradial synostosis, multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome, hydrocephalus, nonsyndromic, autosomal recessive 1, autosomal recessive hydrocephalus due to congenital stenosis of aqueduct of Sylvius, hypertelorism, microtia, facial clefting syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, Vici syndrome, Johanson-Blizzard syndrome, autosomal recessive Kenny-Caffey syndrome, Papillon-Lefevre disease, Haim-Munk syndrome, Laurence-Moon syndrome, Donohue syndrome, lipase deficiency, combined, autosomal recessive familial Mediterranean fever, thiamine-responsive megaloblastic anemia syndrome, cartilage-hair hypoplasia, Nijmegen breakage syndrome, pseudo-TORCH syndrome, Galloway-Mowat syndrome, mulibrey nanism, myotonia congenita, autosomal recessive, Schwartz-Jampel syndrome, proteosome-associated autoinflammatory syndrome, Netherton syndrome, Niemann-Pick disease type A, oculodentodigital dysplasia, autosomal recessive, odonto-onycho-dermal dysplasia, autosomal recessive omodysplasia, osteoporosis-pseudoglioma syndrome, Shwachman-Diamond syndrome, phenylketonuria, Bjornstad syndrome, Laron syndrome, autosomal recessive polycystic kidney disease, autosomal recessive inherited pseudoxanthoma elasticum, autosomal recessive multiple pterygium syndrome, rapadilino syndrome, short-rib thoracic dysplasia 9 with or without polydactyly, autosomal recessive Robinow syndrome, Sjogren-Larsson syndrome, scapuloperoneal spinal muscular atrophy, autosomal recessive, spondyloepiphyseal dysplasia tarda, autosomal recessive, inherited threoninemia, Pendred syndrome, autosomal recessive spondylocostal dysostosis, Werner syndrome, ABCD syndrome, Naxos disease, autosomal recessive amelia, human HOXA1 syndromes, sickle cell disease, autosomal recessive proximal renal tubular acidosis, hyper-IgM syndrome type 2, temtamy preaxial brachydactyly syndrome, TH-deficient dopa-responsive dystonia, craniosynostosis syndrome, autosomal recessive, Niemann-Pick disease type B, skin fragility-woolly hair-palmoplantar keratoderma syndrome, CoQ-responsive OXPHOS deficiency, familial adenomatous polyposis 2, Pierson syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, cardiomyopathy-hypotonia-lactic acidosis syndrome, PHARC syndrome, Kahrizi syndrome, cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies, congenital prothrombin deficiency, immunodeficiency 31B, dyskeratosis congenita, autosomal recessive 2, dyskeratosis congenita, autosomal recessive 3, Nestor-Guillermo progeria syndrome, leukoencephalopathy with calcifications and cysts, mitochondrial pyruvate carrier deficiency, branched-chain keto acid dehydrogenase kinase deficiency, dyskeratosis congenita, autosomal recessive 5, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, alacrima, achalasia, and intellectual disability syndrome, hyperlipoproteinemia, type 1D, microcephaly and chorioretinopathy 2, congenital stationary night blindness 1G, combined oxidative phosphorylation deficiency 29, hypermanganesemia with dystonia 2, growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy, gnb5-related intellectual disability-cardiac arrhythmia syndrome, autosomal recessive spastic paraplegia type 78, autosomal recessive limb-girdle muscular dystrophy, Bardet-Biedl syndrome, autosomal recessive cerebellar ataxia, neuronopathy, distal hereditary motor, autosomal recessive, UV-sensitive syndrome, Ehlers-Danlos syndrome, kyphoscoliotic type 1, Cockayne syndrome, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, leukoencephalopathy-palmoplantar keratoderma syndrome, autosomal recessive hypohidrotic ectodermal dysplasia, Warburg micro syndrome, autosomal recessive primary microcephaly, autosomal recessive progressive external ophthalmoplegia, Meier-Gorlin syndrome, autosomal recessive sideroblastic anemia, autosomal recessive intermediate Charcot-Marie-Tooth disease, Perrault syndrome, autosomal recessive hypophosphatemic rickets, de Barsy syndrome, leukocyte adhesion deficiency, Senior-Loken syndrome, autosomal recessive spastic ataxia, childhood-onset autosomal recessive myopathy with external ophthalmoplegia, autosomal recessive cerebral atrophy, GM3 synthase deficiency, autosomal recessive distal renal tubular acidosis, pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome, autosomal recessive brachyolmia, Aicardi-Goutieres syndrome, homocystinuria without methylmalonic aciduria, Niemann-Pick disease type C, nephronophthisis, autosomal recessive osteopetrosis, peroxisome biogenesis disorder, congenital non-bullous ichthyosiform erythroderma, Seckel syndrome, Usher syndrome, autosomal recessive cutis laxa type 1, autosomal recessive cutis laxa type 2, hearing loss, autosomal recessive, microcephaly, growth restriction, and increased sister chromatid exchange 2, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1, congenital vertebral-cardiac-renal anomalies syndrome, hair defect with photosensitivity and intellectual disability syndrome, autosomal recessive severe congenital neutropenia, severe combined immunodeficiency due to CARMIL2 deficiency, extraoral halitosis due to methanethiol oxidase deficiency, neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, mitochondrial complex 2 deficiency, nuclear type 3, mitochondrial complex 2 deficiency, nuclear type 4, mismatch repair cancer syndrome, spondyloepimetaphyseal dysplasia with joint laxity, type 3, Kilquist syndrome, Duane anomaly-myopathy-scoliosis syndrome, autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome, congenital myopathy with reduced type 2 muscle fibers, NAD(P)HX dehydratase deficiency, autosomal recessive ocular albinism, ichthyosis linearis circumflexa, eosinophil peroxidase deficiency, hyperphenylalaninemia due to DNAJC12 deficiency, autosomal recessive epidermolytic ichthyosis, Ehlers-Danlos syndrome, classic-like, 2, joint laxity, short stature, and myopia, HELIX syndrome, auditory neuropathy-optic atrophy syndrome, glycosylphosphatidylinositol biosynthesis defect 15, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, SCN4A-related myopathy, autosomal recessive, Uner Tan Syndrome, nephropathic cystinosis, Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome type 2, permanent neonatal diabetes mellitus 1, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, Roberts-SC phocomelia syndrome, neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, RPE65-related recessive retinopathy, GUCY2D-related recessive retinopathy, autosomal recessive titinopathy, intellectual disability, autosomal recessive, ALPL-related autosomal recessive hypophosphatasia, spastic paraplegia 18b, autosomal recessive, CEP164-related ciliopathy, RP1-related recessive retinopathy, pseudohypoaldosteronism, type IB2, autosomal recessive, pseudohypoaldosteronism, type IB3, autosomal recessive, spastic paraplegia 30B, autosomal recessive, cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, brain small vessel disease 2B, autosomal recessive, IMPG1-related recessive retinopathy, PROM1-related recessive retinopathy

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

8 retrieved; paginated sample, class counts are floors:

2 pathogenic, 2 uncertain significance, 2 pathogenic/likely pathogenic, 1 benign/likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1685813	NM_005687.5(FARSB):c.1408del (p.Leu470fs)	FARSB	Pathogenic	criteria provided, single submitter
1685814	NM_005687.5(FARSB):c.460A>G (p.Arg154Gly)	FARSB	Pathogenic	criteria provided, single submitter
545501	NM_005687.5(FARSB):c.848+1G>A	FARSB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
559418	NM_005687.5(FARSB):c.853G>A (p.Glu285Lys)	FARSB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4845835	NM_005687.5(FARSB):c.37del (p.Gln13fs)	FARSB	Likely pathogenic	criteria provided, single submitter
4086141	NM_005618.4(DLL1):c.1309G>A (p.Gly437Arg)	DLL1	Uncertain significance	criteria provided, single submitter
487455	NM_005687.5(FARSB):c.767C>T (p.Thr256Met)	FARSB	Uncertain significance	criteria provided, single submitter
1542704	NM_005687.5(FARSB):c.1618+17G>A	FARSB	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 8 · 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
FARSB	Strong	Autosomal recessive	Rajab interstitial lung disease with brain calcifications 1	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FARSB	Orphanet:178506	Interstitial lung disease-brain calcification syndrome
DLL1	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
DLL1	Orphanet:220386	Semilobar holoprosencephaly
DLL1	Orphanet:280195	Septopreoptic holoprosencephaly
DLL1	Orphanet:280200	Microform holoprosencephaly
DLL1	Orphanet:93924	Lobar holoprosencephaly
DLL1	Orphanet:93925	Alobar holoprosencephaly
DLL1	Orphanet:93926	Midline interhemispheric variant of 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
FARSB	HGNC:17800	ENSG00000116120	Q9NSD9	Phenylalanine–tRNA ligase beta subunit	gencc,clinvar
DLL1	HGNC:2908	ENSG00000198719	O00548	Delta-like protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DLL1	Delta-like protein 1	Transmembrane ligand protein of NOTCH1, NOTCH2 and NOTCH3 receptors that binds the extracellular domain (ECD) of Notch receptor in a cis and trans fashion manner.

Protein-family classification

Druggable: 1 · Difficult: 0 · 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)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FARSB	Enzyme (other)	yes	6.1.1.20	Phe-tRNA-synth_IIc_bsu_arc_euk, B3/B4_tRNA-bd, tRNA_synthase_B5-dom
DLL1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, DSL

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
cardiac muscle of right atrium	1
gingival epithelium	1
left ventricle myocardium	1
skin of abdomen	1
spleen	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FARSB	264	ubiquitous	marker	left ventricle myocardium, cardiac muscle of right atrium, gingival epithelium
DLL1	132	broad	marker	spleen, ventricular zone, skin of abdomen

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FARSB	3,392
DLL1	3,147

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FARSB	Q9NSD9	3
DLL1	O00548	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. 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
Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant	1	815.7×	0.010	DLL1
MECP2 regulates transcription of neuronal ligands	1	713.8×	0.010	DLL1
Nephron development	1	439.2×	0.010	DLL1
Constitutive Signaling by NOTCH1 HD Domain Mutants	1	380.7×	0.010	DLL1
NOTCH3 Activation and Transmission of Signal to the Nucleus	1	237.9×	0.010	DLL1
NOTCH2 Activation and Transmission of Signal to the Nucleus	1	219.6×	0.010	DLL1
Cytosolic tRNA aminoacylation	1	219.6×	0.010	FARSB
Formation of paraxial mesoderm	1	203.9×	0.010	DLL1
Activated NOTCH1 Transmits Signal to the Nucleus	1	178.4×	0.010	DLL1
tRNA Aminoacylation	1	142.8×	0.010	FARSB
Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin	1	139.3×	0.010	DLL1
Somitogenesis	1	116.5×	0.011	DLL1
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	98.5×	0.012	DLL1
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	98.5×	0.012	DLL1
Translation	1	31.0×	0.034	FARSB
Metabolism of proteins	1	6.2×	0.155	FARSB

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
cerebellar molecular layer formation	1	8426.0×	0.002	DLL1
regulation of skeletal muscle tissue growth	1	8426.0×	0.002	DLL1
Notch signaling pathway involved in arterial endothelial cell fate commitment	1	8426.0×	0.002	DLL1
cerebellar Purkinje cell layer structural organization	1	4213.0×	0.002	DLL1
negative regulation of epidermal cell differentiation	1	4213.0×	0.002	DLL1
loop of Henle development	1	4213.0×	0.002	DLL1
endothelial tip cell fate specification	1	4213.0×	0.002	DLL1
lateral inhibition	1	2808.7×	0.002	DLL1
inhibition of neuroepithelial cell differentiation	1	2106.5×	0.002	DLL1
phenylalanyl-tRNA aminoacylation	1	2106.5×	0.002	FARSB
compartment pattern specification	1	2106.5×	0.002	DLL1
negative regulation of inner ear auditory receptor cell differentiation	1	2106.5×	0.002	DLL1
skin epidermis development	1	2106.5×	0.002	DLL1
regulation of vascular endothelial growth factor signaling pathway	1	2106.5×	0.002	DLL1
somite specification	1	1685.2×	0.002	DLL1
positive regulation of skeletal muscle tissue growth	1	1685.2×	0.002	DLL1
proximal tubule development	1	1685.2×	0.002	DLL1
regulation of somitogenesis	1	1404.3×	0.002	DLL1
regulation of vascular endothelial growth factor receptor signaling pathway	1	1404.3×	0.002	DLL1
skeletal muscle tissue growth	1	1404.3×	0.002	DLL1
negative regulation of cardiac muscle cell differentiation	1	1203.7×	0.003	DLL1
marginal zone B cell differentiation	1	936.2×	0.003	DLL1
negative regulation of glial cell apoptotic process	1	936.2×	0.003	DLL1
retina morphogenesis in camera-type eye	1	936.2×	0.003	DLL1
nephron development	1	936.2×	0.003	DLL1
neuroepithelial cell differentiation	1	766.0×	0.003	DLL1
type B pancreatic cell development	1	648.1×	0.004	DLL1
negative regulation of epithelial cell differentiation	1	601.9×	0.004	DLL1
inner ear auditory receptor cell differentiation	1	601.9×	0.004	DLL1
left/right axis specification	1	601.9×	0.004	DLL1

Therapeutics

Drug target analysis

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

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
FARSB	3	2
DLL1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	FARSB
TANDUTINIB	2	FARSB
PHA-793887	1	FARSB

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
FARSB	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FARSB	6.1.1.20	phenylalanine-tRNA ligase

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

3 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	FARSB
TANDUTINIB	2	FARSB
PHA-793887	1	FARSB

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	FARSB
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	DLL1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DLL1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.