SHOX

protein-coding

short stature homeobox, the group of Pseudoautosomal region 1|PRD class homeoboxes and pseudogenes

Gene summary

This gene belongs to the paired homeobox family and is located in the pseudoautosomal region 1 (PAR1) of X and Y chromosomes. Defects in this gene are associated with idiopathic growth retardation and in the short stature phenotype of Turner syndrome patients. This gene is highly conserved across species from mammals to fish to flies. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

N/A

Inheritance

XL, AD, AR, PAR

ClinVar variants

P:72U:152B:28

Top phenotype

Langer mesomelic dysplasia; Leri-Weill dyschondrosteosis; Short stature, idiopathic familial

gnomAD constraint

pLI —, LoF o/e 0.16

Max pathogenic AF

—

Genomic locus

chrY:624,344-659,411

External References & Databases

Ensembl (ENSG00000292354)

NCBI Gene (6473)

OMIM (312865, 400020)

Transcript & Mutation Effects

hg38 • Region Span ~35.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Leri-Weill dyschondrosteosisSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0007481

Submitter: Labcorp Genetics (formerly Invitae)

Leri-Weill dyschondrosteosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007481

Submitter: Orphanet

Leri-Weill dyschondrosteosisDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0007481

Submitter: Ambry Genetics

Langer mesomelic dysplasiaSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0009588

Submitter: Labcorp Genetics (formerly Invitae)

Langer mesomelic dysplasiaMODERATE

Inheritance Pattern: Unknown

Disease ID:MONDO:0009588

Submitter: Ambry Genetics

Leri-Weill dyschondrosteosisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007481

Submitter: PanelApp Australia

Leri-Weill dyschondrosteosisDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0007481

Submitter: G2P

Langer mesomelic dysplasiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009588

Submitter: Orphanet

SHOX-related short statureSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0010367

Submitter: Orphanet

Langer mesomelic dysplasiaDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0009588

Submitter: G2P

Langer mesomelic dysplasiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009588

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Langer mesomelic dysplasia; Leri-Weill dyschondrosteosis; Short stature, idiopathic familialXL/PAR

Manifestation: Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: GH treatment can be effective in idiopathic short stature; Deletion of regulatory elements can also produce manifestations

Refs: 14344358; 5410085; 6059604; 7365762; 9140395; 9590292; 9590293; 11030412; 11186941; 10713888; 11403039; 11739418; 11932348; 14557470; 12784295; 15173249; 15173321; 15214013; 16227037; 17935511; 17047016; 17200153; 19578035; 19636220; 20301394; 20412871; 20538086; 20683993; 21712857; 21912078; 22020182; 22071895; 22461651; 22518848; 22572840

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SHOX variants in ClinVar

5 Conditions Cataloged

not providedTotal: 28

Leri-Weill dyschondrosteosisTotal: 26

SHOX-related disorderTotal: 4

Langer mesomelic dysplasia syndromeTotal: 2

SHOX-related short statureTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript . Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			10 clinvar	16 clinvar	10 clinvar	36
missense	10 clinvar	10 clinvar	136 clinvar	2 clinvar		158
nonsense	12 clinvar	12 clinvar	2 clinvar			26
start loss						0
frameshift	16 clinvar	8 clinvar				24
splice donor/acceptor (+/-2bp)	2 clinvar	2 clinvar	4 clinvar			8
Total	40	32	152	18	10	252

Highest pathogenic variant AF is 0.0000131472

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
ENST00000686671.1	Ensembl	ENSP00000508521.1	5	MANE Select
NM_000451.4	RefSeq	NP_000442.1	10	Standard
NM_006883.2	RefSeq	NP_006874.1	10	Standard
ENST00000334060.8	Ensembl	ENSP00000335505.3	5	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
shox	Danio rerio	Structure: cranial vault Quality: decreased process quality abnormal

Gene / Model

Organism

Observed Phenotype

shox

Danio rerio

Structure: cranial vault

Quality: decreased process quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

skeletal system development
transcription by RNA polymerase II
positive regulation of transcription by RNA polymerase II

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription activator activity, RNA polymerase II-specific
DNA-binding transcription factor activity
protein binding
sequence-specific DNA binding

Cellular Component

nucleoplasm
intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000381578
Coding exons: 5
Length: 35068
Individuals with no LoFs: 125580
Homozygous LoFs: 0
Heterozygous LoFs: 6
Defined: 125586
p: 0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.538	168	149	1.12	0.00000750	1887
Missense (PolyPhen)		44	56.999	0.77195		736
Synonymous	-3.41	97	62.6	1.55	0.00000334	577
Loss of Function	2.71	2	12.2	0.164	5.85e-7	135

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000055	0.000053	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Controls fundamental aspects of growth and development.;
Disease: DISEASE: Leri-Weill dyschondrosteosis (LWD) [MIM:127300]: Dominantly inherited skeletal dysplasia characterized by moderate short stature predominantly because of short mesomelic limb segments. It is often associated with the Madelung deformity of the wrist, comprising bowing of the radius and dorsal dislocation of the distal ulna. {ECO:0000269|PubMed:11030412, ECO:0000269|PubMed:11403039}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Langer mesomelic dysplasia (LMD) [MIM:249700]: Autosomal recessive rare skeletal dysplasia characterized by severe short stature owing to shortening and maldevelopment of the mesomelic and rhizomelic segments of the limbs. Associated malformations are rarely reported and intellect is normal in all affected subjects reported to date. {ECO:0000269|PubMed:11889214}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Short stature, idiopathic, X-linked (ISS) [MIM:300582]: A condition defined by a standing height more than 2 standard deviations below the mean (or below the 2.5 percentile) for sex and chronological age, compared with a well-nourished, genetically relevant population, in the absence of specific causative disorders. {ECO:0000269|PubMed:9140395}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Essentials

Essential (CRISPR): N
Indispensability pred.: E
Indispensability score: 0.731

Gene Damage Prediction

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