lethal short-limb skeletal dysplasia, Al Gazali type

Summary

lethal short-limb skeletal dysplasia, Al Gazali type (MONDO:0011051) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 14
• Phenotypes (HPO): 31

Clinical features

Signs & symptoms

Clinical features (HPO)

31 HPO clinical features (Orphanet curated; top 31 by frequency):

HPO ID	Term	Frequency
HP:0000239	Large fontanelles	Very frequent (80-99%)
HP:0000316	Hypertelorism	Very frequent (80-99%)
HP:0000377	Abnormal pinna morphology	Very frequent (80-99%)
HP:0000470	Short neck	Very frequent (80-99%)
HP:0000885	Broad ribs	Very frequent (80-99%)
HP:0001156	Brachydactyly	Very frequent (80-99%)
HP:0001561	Polyhydramnios	Very frequent (80-99%)
HP:0001773	Short foot	Very frequent (80-99%)
HP:0001831	Short toe	Very frequent (80-99%)
HP:0004482	Relative macrocephaly	Very frequent (80-99%)
HP:0005280	Depressed nasal bridge	Very frequent (80-99%)
HP:0005789	Generalized osteosclerosis	Very frequent (80-99%)
HP:0009106	Abnormal pelvis bone ossification	Very frequent (80-99%)
HP:0009381	Short finger	Very frequent (80-99%)
HP:0009826	Limb undergrowth	Very frequent (80-99%)
HP:0010034	Short 1st metacarpal	Very frequent (80-99%)
HP:0031096	Delayed vertebral ossification	Very frequent (80-99%)
HP:0200055	Small hand	Very frequent (80-99%)
HP:0000219	Thin upper lip vermilion	Frequent (30-79%)
HP:0000926	Platyspondyly	Frequent (30-79%)
HP:0000998	Hypertrichosis	Frequent (30-79%)
HP:0001072	Thickened skin	Frequent (30-79%)
HP:0001387	Joint stiffness	Frequent (30-79%)
HP:0001511	Intrauterine growth retardation	Frequent (30-79%)
HP:0001642	Pulmonic stenosis	Frequent (30-79%)
HP:0001762	Talipes equinovarus	Frequent (30-79%)
HP:0001789	Hydrops fetalis	Frequent (30-79%)
HP:0002089	Pulmonary hypoplasia	Frequent (30-79%)
HP:0011800	Midface retrusion	Frequent (30-79%)
HP:0002645	Wormian bones	Occasional (5-29%)
HP:0003038	Fibular hypoplasia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	lethal short-limb skeletal dysplasia, Al Gazali type
Mondo ID	MONDO:0011051
MeSH	C537598
OMIM	601356
Orphanet	646136
UMLS	C1832435
MedGen	330467
GARD	0004827
Is cancer (heuristic)	no

Also known as: dysplastic cortical hyperostosis, Al-Gazali type · lethal neonatal short limb dwarfism · lethal short limb skeletal dysplasia Al Gazali type · lethal short-limb skeletal dysplasia, Al Gazali type

Data availability: 14 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › osteochondrodysplasia › neonatal osteosclerotic dysplasia › dysplastic cortical hyperostosis › lethal short-limb skeletal dysplasia, Al Gazali type

Related subtypes (1): dysplastic cortical hyperostosis, Kozlowski-Tsuruta type

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

14 retrieved; paginated sample, class counts are floors:

8 likely pathogenic, 6 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1164089	NM_014694.4(ADAMTSL2):c.337C>T (p.Arg113Cys)	ADAMTSL2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1710157	NM_014694.4(ADAMTSL2):c.1061del (p.Gly354fs)	ADAMTSL2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1710160	NM_014694.4(ADAMTSL2):c.502G>A (p.Gly168Ser)	ADAMTSL2	Likely pathogenic	criteria provided, single submitter
1710162	NM_014694.4(ADAMTSL2):c.229C>T (p.Gln77Ter)	ADAMTSL2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1710163	NM_014694.4(ADAMTSL2):c.800G>T (p.Gly267Val)	ADAMTSL2	Likely pathogenic	criteria provided, single submitter
1710164	NM_014694.4(ADAMTSL2):c.496C>T (p.Arg166Cys)	ADAMTSL2	Likely pathogenic	criteria provided, single submitter
1710165	NM_014694.4(ADAMTSL2):c.718C>T (p.Arg240Ter)	ADAMTSL2	Likely pathogenic	criteria provided, single submitter
694	NM_014694.4(ADAMTSL2):c.338G>A (p.Arg113His)	ADAMTSL2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1334607	NM_014694.4(ADAMTSL2):c.1934G>A (p.Arg645His)	ADAMTSL2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1334608	NM_014694.4(ADAMTSL2):c.-151+2T>C	ADAMTSL2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1710156	NM_014694.4(ADAMTSL2):c.157T>C (p.Trp53Arg)	ADAMTSL2	Uncertain significance	criteria provided, single submitter
1710158	NM_014694.4(ADAMTSL2):c.1998C>G (p.Cys666Trp)	ADAMTSL2	Uncertain significance	criteria provided, single submitter
1710159	NM_014694.4(ADAMTSL2):c.2137T>C (p.Cys713Arg)	ADAMTSL2	Uncertain significance	criteria provided, single submitter
1710161	NM_014694.4(ADAMTSL2):c.2626C>G (p.Arg876Gly)	ADAMTSL2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ADAMTSL2	Orphanet:1901	Dermatosparaxis Ehlers-Danlos syndrome
ADAMTSL2	Orphanet:2623	Geleophysic dysplasia

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ADAMTSL2	HGNC:14631	ENSG00000197859	Q86TH1	ADAMTS-like protein 2	clinvar

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ADAMTSL2	Other/Unknown	no		TSP1_rpt, ADAMTS_spacer1, PLAC

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cardiac atrium	1
metanephros cortex	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ADAMTSL2	159	broad	marker	right atrium auricular region, metanephros cortex, cardiac atrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ADAMTSL2	600

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ADAMTSL2	Q86TH1	67.10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 1 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
Defective B3GALTL causes PpS	1	308.6×	0.014	ADAMTSL2
O-glycosylation of TSR domain-containing proteins	1	300.5×	0.014	ADAMTSL2
Diseases associated with O-glycosylation of proteins	1	215.5×	0.014	ADAMTSL2
O-linked glycosylation	1	144.6×	0.014	ADAMTSL2
Diseases of glycosylation	1	131.3×	0.014	ADAMTSL2
Diseases of metabolism	1	80.4×	0.019	ADAMTSL2
Post-translational protein modification	1	19.2×	0.067	ADAMTSL2
Disease	1	13.1×	0.081	ADAMTSL2
Metabolism of proteins	1	12.4×	0.081	ADAMTSL2

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
lobar bronchus epithelium development	1	16852.0×	2e-04	ADAMTSL2
negative regulation of transforming growth factor beta receptor signaling pathway	1	173.7×	0.008	ADAMTSL2
extracellular matrix organization	1	122.1×	0.008	ADAMTSL2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ADAMTSL2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	1	ADAMTSL2

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)
ADAMTSL2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.