LHX4

LIM homeobox 4, the group of LIM class homeoboxes

Basic information

Region (hg38): 1:180230263-180278984

Links

ENSG00000121454 ∙ NCBI:89884 ∙ OMIM:602146 ∙ HGNC:21734 ∙ Uniprot:Q969G2 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• short stature-pituitary and cerebellar defects-small sella turcica syndrome (Moderate), mode of inheritance: AD
• short stature-pituitary and cerebellar defects-small sella turcica syndrome (Strong), mode of inheritance: AD
• short stature-pituitary and cerebellar defects-small sella turcica syndrome (Definitive), mode of inheritance: AD
• short stature-pituitary and cerebellar defects-small sella turcica syndrome (Supportive), mode of inheritance: AD
• combined pituitary hormone deficiencies, genetic form (Supportive), mode of inheritance: AD
• pituitary stalk interruption syndrome (Supportive), mode of inheritance: AD
• hypothyroidism due to deficient transcription factors involved in pituitary development or function (Supportive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Pituitary hormone deficiency, combined, 4	AD	Endocrine	Individuals can prevent neonatally with severe manifestations due to endocrine anomalies such as hypoglycemia; Respiratory distress has also been described at presentation; Other corrections of endocrine anomalies, such as growth hormone deficiency treatment, can be beneficial	Endocrine; Musculoskeletal; Neurologic; Pulmonary	11567216; 17527005; 18073311; 19856252; 20534763; 22232309; 23029363; 23761422

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the LHX4 gene.

• not provided (70 variants)
• Short stature-pituitary and cerebellar defects-small sella turcica syndrome (64 variants)
• Inborn genetic diseases (11 variants)
• not specified (10 variants)
• Combined Pituitary Hormone Deficiency, Dominant (2 variants)
• LHX4-related condition (1 variants)
• See cases (1 variants)
• Pituitary hormone deficiency, combined, 1 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the LHX4 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	19	2	22
missense		1	44	5	3	53
nonsense		1				1
start loss						0
frameshift	2					2
inframe indel			3	1		4
splice donor/acceptor (+/-2bp)	1	1				2
splice region			1	1	2	4
non coding			15	1	18	34
Total	3	3	63	26	23

Highest pathogenic variant AF is 0.00000657

Variants in LHX4

This is a list of pathogenic ClinVar variants found in the LHX4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
1-180230309-G-A		Short stature-pituitary and cerebellar defects-small sella turcica syndrome	Uncertain significance (Jan 13, 2018)
1-180230358-A-G		Short stature-pituitary and cerebellar defects-small sella turcica syndrome	Uncertain significance (Jan 13, 2018)
1-180230396-G-C		Short stature-pituitary and cerebellar defects-small sella turcica syndrome	Uncertain significance (Jan 12, 2018)
1-180230409-T-G		Short stature-pituitary and cerebellar defects-small sella turcica syndrome	Uncertain significance (Jan 13, 2018)
1-180230410-C-T		Short stature-pituitary and cerebellar defects-small sella turcica syndrome	Benign (Jan 13, 2018)
1-180230530-A-G		LHX4-related disorder	Uncertain significance (Dec 13, 2023)
1-180230565-TGTC-T		Short stature-pituitary and cerebellar defects-small sella turcica syndrome	Uncertain significance (Mar 31, 2022)
1-180230566-G-A		Inborn genetic diseases • not specified • Short stature-pituitary and cerebellar defects-small sella turcica syndrome	Conflicting classifications of pathogenicity (Jul 12, 2023)
1-180230579-C-T		not specified	Uncertain significance (Mar 04, 2024)
1-180230592-T-C		Short stature-pituitary and cerebellar defects-small sella turcica syndrome	Benign (Jan 05, 2024)
1-180230614-C-G			Likely benign (Feb 27, 2023)
1-180248001-G-A			Benign (Jun 19, 2021)
1-180248017-C-T			Benign (Jun 19, 2021)
1-180248057-C-A			Benign (Jun 19, 2021)
1-180248115-C-T			Benign (Jun 19, 2021)
1-180248265-C-A			Benign (Dec 13, 2023)
1-180248283-A-G			Likely pathogenic (Sep 18, 2022)
1-180248291-C-T		Short stature-pituitary and cerebellar defects-small sella turcica syndrome	Uncertain significance (Jan 13, 2018)
1-180248298-C-G		Short stature-pituitary and cerebellar defects-small sella turcica syndrome	Uncertain significance (Jun 26, 2019)
1-180248298-C-T		Short stature-pituitary and cerebellar defects-small sella turcica syndrome • LHX4-related disorder	Benign/Likely benign (Jun 16, 2021)
1-180248299-G-A		Combined Pituitary Hormone Deficiency, Dominant • Inborn genetic diseases	Uncertain significance (Oct 13, 2023)
1-180248331-C-T			Likely benign (Aug 11, 2018)
1-180248354-A-G		Short stature-pituitary and cerebellar defects-small sella turcica syndrome • Inborn genetic diseases	Conflicting classifications of pathogenicity (Sep 12, 2023)
1-180248376-G-A			Likely benign (Aug 22, 2022)
1-180248379-T-G		See cases	Likely pathogenic (Apr 26, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
LHX4	protein_coding	protein_coding	ENST00000263726	6	49960

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0175	0.978	125734	0	14	125748	0.0000557

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.670	205	234	0.877	0.0000143	2584
Missense in Polyphen		76	88.8	0.85585		992
Synonymous	-0.479	100	94.1	1.06	0.00000610	749
Loss of Function	2.51	6	17.3	0.348	8.53e-7	193

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000116	0.000116
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.000109	0.000109
Finnish	0.00	0.00
European (Non-Finnish)	0.0000265	0.0000264
Middle Eastern	0.000109	0.000109
South Asian	0.000131	0.000131
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: May play a critical role in the development of respiratory control mechanisms and in the normal growth and maturation of the lung. Binds preferentially to methylated DNA (PubMed:28473536). {ECO:0000250, ECO:0000269|PubMed:28473536}.
• Disease: DISEASE: Pituitary hormone deficiency, combined, 4 (CPHD4) [MIM:262700]: Combined pituitary hormone deficiency is defined as the impaired production of growth hormone and one or more of the other five anterior pituitary hormones. CPHD4 is characterized by complete or partial deficiencies of growth hormone, thyroid- stimulating hormone, luteinizing hormone, follicle stimulating hormone and adrenocorticotropic hormone. Clinical features include short stature, cerebellar defects, and small sella turcica. {ECO:0000269|PubMed:17527005, ECO:0000269|PubMed:18073311}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=A chromosomal aberration involving LHX4 may be a cause of acute lymphoblastic leukemia. Translocation t(1;14)(q25;q32) with IGHG1. {ECO:0000269|PubMed:11567216}.
• Pathway: Developmental Biology;Regulation of expression of SLITs and ROBOs;Signaling by ROBO receptors;Axon guidance (Consensus)

Recessive Scores

• pRec: 0.204

Intolerance Scores

• loftool: 0.155
• rvis_EVS: -0.45
• rvis_percentile_EVS: 24.33

Haploinsufficiency Scores

• pHI: 0.349
• hipred: Y
• hipred_score: 0.625
• ghis: 0.532

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.945

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Lhx4
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); respiratory system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); homeostasis/metabolism phenotype; endocrine/exocrine gland phenotype

Gene ontology

• Biological process: placenta development;motor neuron axon guidance;animal organ morphogenesis;medial motor column neuron differentiation;negative regulation of apoptotic process;positive regulation of transcription by RNA polymerase II
• Cellular component: nucleus
• Molecular function: DNA-binding transcription factor activity, RNA polymerase II-specific;DNA-binding transcription activator activity, RNA polymerase II-specific;protein binding;methyl-CpG binding;sequence-specific DNA binding;metal ion binding