Alopecia-intellectual disability syndrome 4

Summary

Alopecia-intellectual disability syndrome 4 (MONDO:0030009) is a disease caused by LSS (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: LSS (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 31

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	alopecia-intellectual disability syndrome 4
Mondo ID	MONDO:0030009
OMIM	618840
DOID	DOID:0080950
UMLS	C5394241
MedGen	1713432
GARD	0016386
Is cancer (heuristic)	no

Also known as: alopecia-intellectual disability syndrome 4 · ALOPECIA-MENTAL RETARDATION SYNDROME 4 · alopecia-mental retardation syndrome 4 · APMR4

Data availability: 31 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › alopecia - intellectual disability syndrome › alopecia-intellectual disability syndrome 4

Related subtypes (3): alopecia-intellectual disability syndrome 2, alopecia-intellectual disability syndrome 3, alopecia-intellectual disability syndrome 1

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

31 retrieved; paginated sample, class counts are floors:

11 pathogenic, 6 likely pathogenic, 5 benign, 4 uncertain significance, 2 benign/likely benign, 2 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1707554	NC_000021.9:g.46228667_46229005del	LOC112694753	Pathogenic	criteria provided, single submitter
1256057	NM_002340.6(LSS):c.647G>A (p.Trp216Ter)	LSS	Pathogenic	criteria provided, multiple submitters, no conflicts
1526304	NM_002340.6(LSS):c.530G>A (p.Arg177Gln)	LSS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1707553	NM_002340.6(LSS):c.1955C>T (p.Thr652Ile)	LSS	Pathogenic	criteria provided, single submitter
2500989	NM_002340.6(LSS):c.1522G>C (p.Gly508Arg)	LSS	Pathogenic	criteria provided, single submitter
2500990	NM_002340.6(LSS):c.1016C>T (p.Ser339Leu)	LSS	Pathogenic	criteria provided, single submitter
599321	NM_002340.6(LSS):c.304C>G (p.Leu102Val)	LSS	Pathogenic	criteria provided, single submitter
599322	NM_002340.6(LSS):c.423G>A (p.Trp141Ter)	LSS	Pathogenic	no assertion criteria provided
834065	NM_002340.6(LSS):c.2114C>A (p.Thr705Lys)	LSS	Pathogenic	no assertion criteria provided
834066	NM_002340.6(LSS):c.779G>C (p.Arg260Pro)	LSS	Pathogenic	no assertion criteria provided
834068	NM_002340.6(LSS):c.35G>A (p.Gly12Asp)	LSS	Pathogenic	no assertion criteria provided
982379	NM_002340.6(LSS):c.1109+2T>C	LSS	Pathogenic	criteria provided, single submitter
982382	NM_016284.5(CNOT1):c.3681_3687del (p.Lys1227fs)	CNOT1	Likely pathogenic	criteria provided, single submitter
1098866	NM_002340.6(LSS):c.429-1G>A	LSS	Likely pathogenic	criteria provided, single submitter
1256056	NM_002340.6(LSS):c.857A>G (p.Tyr286Cys)	LSS	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4072283	NM_002340.6(LSS):c.523C>T (p.Arg175Ter)	LSS	Likely pathogenic	criteria provided, single submitter
599323	NM_002340.6(LSS):c.625A>T (p.Asn209Tyr)	LSS	Likely pathogenic	criteria provided, single submitter
834064	NM_002340.6(LSS):c.1547A>G (p.Asn516Ser)	LSS	Likely pathogenic	criteria provided, single submitter
221226	NM_002340.6(LSS):c.1762G>A (p.Gly588Ser)	LSS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
834067	NM_002340.6(LSS):c.1194+5G>A	LSS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1701718	NM_002340.6(LSS):c.1194G>A (p.Glu398=)	LSS	Uncertain significance	criteria provided, single submitter
1701719	NM_002340.6(LSS):c.22C>G (p.Arg8Gly)	LSS	Uncertain significance	criteria provided, single submitter
3250416	NM_002340.6(LSS):c.1153C>G (p.Gln385Glu)	LSS	Uncertain significance	criteria provided, single submitter
4072298	NM_002340.6(LSS):c.673C>T (p.His225Tyr)	LSS	Uncertain significance	criteria provided, single submitter
1201735	NM_002340.6(LSS):c.181-27dup	LSS	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1287852	NM_002340.6(LSS):c.181-16_181-15del	LSS	Benign	criteria provided, multiple submitters, no conflicts
677172	NM_002340.6(LSS):c.551-6G>C	LSS	Benign	criteria provided, multiple submitters, no conflicts
677173	NM_002340.6(LSS):c.784-6C>T	LSS	Benign	criteria provided, multiple submitters, no conflicts
677174	NM_002340.6(LSS):c.864G>C (p.Pro288=)	LSS	Benign	criteria provided, multiple submitters, no conflicts
677175	NM_002340.6(LSS):c.1924T>G (p.Leu642Val)	LSS	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 6 · 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
LSS	Strong	Autosomal recessive	alopecia-intellectual disability syndrome 4	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LSS	Orphanet:1366	Autosomal recessive palmoplantar keratoderma and congenital alopecia
LSS	Orphanet:2850	Alopecia-intellectual disability syndrome
LSS	Orphanet:55654	Hypotrichosis simplex
LSS	Orphanet:98994	Total early-onset cataract
CNOT1	Orphanet:528084	Non-specific syndromic intellectual disability
CNOT1	Orphanet:556955	Pancreatic agenesis-holoprosencephaly syndrome

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
LSS	HGNC:6708	ENSG00000160285	P48449	Lanosterol synthase	gencc,clinvar
CNOT1	HGNC:7877	ENSG00000125107	A5YKK6	CCR4-NOT transcription complex subunit 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LSS	Lanosterol synthase	Key enzyme in the cholesterol biosynthesis pathway.
CNOT1	CCR4-NOT transcription complex subunit 1	Scaffolding component of the CCR4-NOT complex which is one of the major cellular mRNA deadenylases and is linked to various cellular processes including bulk mRNA degradation, miRNA-mediated repression, translational repression during tran…

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)
LSS	Enzyme (other)	yes	5.4.99.7	Terpene_synthase_CS, Terpenoid_cyclase/PrenylTrfase, Squalene_cyclase
CNOT1	Other/Unknown	no		CCR4-Not_Not1_C, CNOT1_dom_4, CNOT1_CAF1_bind

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
C1 segment of cervical spinal cord	1
mucosa of stomach	1
skin of leg	1
left testis	1
primordial germ cell in gonad	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LSS	134	ubiquitous	marker	mucosa of stomach, C1 segment of cervical spinal cord, skin of leg
CNOT1	295	ubiquitous	marker	primordial germ cell in gonad, left testis, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CNOT1	3,760
LSS	1,562

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CNOT1	A5YKK6	21
LSS	P48449	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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
Cholesterol biosynthesis	1	571.0×	0.010	LSS
Lanosterol biosynthesis	1	380.7×	0.010	LSS
TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain	1	259.6×	0.010	CNOT1
Deadenylation of mRNA	1	219.6×	0.010	CNOT1
M-decay: degradation of maternal mRNAs by maternally stored factors	1	163.1×	0.010	CNOT1
Regulation of cholesterol biosynthesis by SREBP (SREBF)	1	158.6×	0.010	LSS
Activation of gene expression by SREBF (SREBP)	1	129.8×	0.011	LSS
Metabolism of steroids	1	68.8×	0.018	LSS
Metabolism of lipids	1	15.8×	0.069	LSS
Metabolism	1	5.8×	0.165	LSS

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
triterpenoid biosynthetic process	1	8426.0×	0.002	LSS
positive regulation of cytoplasmic mRNA processing body assembly	1	1203.7×	0.003	CNOT1
negative regulation of retinoic acid receptor signaling pathway	1	766.0×	0.003	CNOT1
regulation of stem cell population maintenance	1	702.2×	0.003	CNOT1
miRNA-mediated post-transcriptional gene silencing	1	648.1×	0.003	CNOT1
positive regulation of nuclear-transcribed mRNA poly(A) tail shortening	1	648.1×	0.003	CNOT1
positive regulation of mRNA catabolic process	1	601.9×	0.003	CNOT1
negative regulation of intracellular estrogen receptor signaling pathway	1	561.7×	0.003	CNOT1
positive regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay	1	561.7×	0.003	CNOT1
nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay	1	526.6×	0.003	CNOT1
trophectodermal cell differentiation	1	495.6×	0.003	CNOT1
nuclear-transcribed mRNA poly(A) tail shortening	1	401.2×	0.004	CNOT1
steroid biosynthetic process	1	300.9×	0.004	LSS
cholesterol biosynthetic process	1	210.7×	0.006	LSS
negative regulation of translation	1	98.0×	0.012	CNOT1
regulation of protein stability	1	62.9×	0.017	LSS
negative regulation of transcription by RNA polymerase II	1	8.9×	0.110	CNOT1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LSS	0	0
CNOT1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
LSS	46	Binding:45, Functional:1
CNOT1	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
LSS	5.4.99.7	Lanosterol synthase

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	1	LSS
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CNOT1

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)
LSS	46	—
CNOT1	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.