LMX1A

Chr 1AD

LIM homeobox transcription factor 1 alpha

Also known as: DFNA7, LMX1, LMX1.1

NCBI Gene: 4009 ENSG00000162761 UniProt: Q8TE12 OMIM: 600298

LMX1A encodes a transcription factor that activates insulin gene transcription and is required for roof plate development in the central nervous system and specification of dorsal cell fates during embryogenesis. Mutations cause autosomal dominant nail-patella syndrome, characterized by nail dysplasia, absent or hypoplastic patellae, elbow abnormalities, and nephropathy. The gene is highly constrained against loss-of-function variants, indicating that haploinsufficiency is likely pathogenic.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a homeodomain and LIM-domain containing protein. The encoded protein is a transcription factor that acts as a positive regulator of insulin gene transcription. This gene also plays a role in the development of dopamine producing neurons during embryogenesis. Mutations in this gene are associated with an increased risk of developing Parkinson's disease. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.271 OMIM phenotype

Clinical Summary— LMX1A

🧬

Gene-Disease Validity (ClinGen)

autosomal dominant nonsyndromic hearing loss · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

📋

ClinVar Variants

10 unique Pathogenic / Likely Pathogenic· 63 VUS of 104 total submissions

💊

Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.27LOEUF

pLI 0.991

Z-score 4.06

OE 0.09 (0.04–0.27)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.00Z-score

OE missense 0.81 (0.71–0.92)

175 obs / 216.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.09 (0.04–0.27)

0≤0.351.4

Missense OE?0.81 (0.71–0.92)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 2 / 23.0Missense obs/exp: 175 / 216.5Syn Z: 0.56

This gene — mechanism propensity

0.4686th %ile

GOF

0.3887th %ile

LOF

0.76top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 60% of P/LP variants are LoF · LOEUF 0.27

Literature Evidence

LOFFurther, our dominant LMX1A variant exerted pathogenic effects via haploinsufficiency rather than dominant-negative effect.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 32840933 ↗

ClinVar Variant Classifications

104 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic5

VUS63

Likely Benign9

Benign19

Conflicting2

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	3	0	0	5
Likely Pathogenic	4	1	0	0	5
VUS	3	58	1	1	63
Likely Benign	0	2	3	4	9
Benign	0	0	14	5	19
Conflicting	—				2
Total	9	64	18	10	103

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

19 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap LMX1A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →