KIDINS220

protein-coding

kinase D interacting substrate 220, the group of Ankyrin repeat domain containing

Gene summary

This gene encodes a transmembrane protein that is preferentially expressed in the nervous system where it controls neuronal cell survival, differentiation into exons and dendrites, and synaptic plasticity. The encoded protein interacts with membrane receptors, cytosolic signaling components, and cytoskeletal proteins, serving as a scaffold that mediates crosstalk between the neurotrophin pathway and several other intracellular signaling pathways. Aberrant expression of this gene is associated with the onset of various neuropsychiatric disorders and neurodegenerative diseases, including Alzheimer's disease. Naturally occurring mutations in this gene are associated with a syndrome characterized by spastic paraplegia, intellectual disability, nystagmus and obesity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2017]

MANE transcript

NM_020738.4

Inheritance

AR, AD

ClinVar variants

P:70U:708B:363

Top phenotype

Spastic paraplegia, intellectual disability, nystagmus, and obesity (SINO); Ventriculomegaly and arthrogryposis

gnomAD constraint

pLI —, LoF o/e 0.24

Max pathogenic AF

—

Genomic locus

chr2:8,721,081-8,837,630

External References & Databases

Ensembl (ENSG00000134313)

Transcript & Mutation Effects

hg38 • Region Span ~116.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ventriculomegaly and arthrogryposisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859184

Submitter: PanelApp Australia

ventriculomegaly and arthrogryposisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859184

Submitter: Labcorp Genetics (formerly Invitae)

spastic paraplegia, intellectual disability, nystagmus, and obesitySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0015007

Submitter: G2P

spastic paraplegia, intellectual disability, nystagmus, and obesitySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0015007

Submitter: PanelApp Australia

ventriculomegaly and arthrogryposisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0859184

Submitter: ClinGen

KIDINS220 was first reported in relation to autosomal dominant VENARG (ventriculomegaly and arthrogryposis) in 2017 (Mero et al., PMID: 28934391). This condition is associated with ventriculomegaly, cerebellar hypoplasia, and other brain anomalies; as well as joint contractures and congenital heart disease. VENARG is neonatal lethal, and features of the condition have been evident in ultrasounds of affected probands earlier than 12 weeks gestation. The gene is also associated with autosomal dominant SINO (spastic paraplegia, intellectual disability, nystagmus, and obesity), an assertion first made in 2016 by Josifova et al (PMID: 27005418). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities: VENARG (OMIM:619501) & SINO (OMIM: 617296). The split curation for autosomal dominant SINO has been done separately. 5 variants (in-frame deletion, frameshift, splicing) that have been reported in at least 8 probands in 4 publications (PMIDs: 28934391, 32909676, 33205811, 36588759) are included in this curation. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (mouse models, expression analysis; PMIDs: 19449316, 22048169, 34002021, 35140204). Mouse analysis indicates expression of KIDINS220 within the brain, specifically in the pyramidal neurons and hippocampus. Mouse models indicate ventriculomegaly, reduced dendritic complexity, memory issues, and abnormal heart morphology in mutants. In summary, there is definitive evidence supporting the relationship between KIDINS220 and autosomal dominant VENARG. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Prenatal GCEP on the meeting date 9/4/2024 (SOP Version 10).

spastic paraplegia, intellectual disability, nystagmus, and obesitySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015007

Submitter: Orphanet

spastic paraplegia, intellectual disability, nystagmus, and obesityDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015007

Submitter: ClinGen

*KIDINS220* was first reported in relation to autosomal dominant spastic paraplegia, intellectual disability, nystagmus, and obesity (SINO) in 2016 (Josifova et al., PMID: 27005418). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities: SINO (OMIM: 617296) & ventriculomegaly and arthrogryposis (VENARG OMIM:619501). The split curation for autosomal recessive VENARG has been curated separately. 19 variants (missense, nonsense, frameshift) that have been reported in at least 25 probands in 11 publications (PMIDs: 27005418, 29667355, 30542205, 31130284, 31630374, 31618753, 33763417, 36368352, 37642312, 39033379, 39336781) are included in this curation. The mechanism of pathogenicity appears to be dominant negative (PMID: 39033379). SINO is caused by variants that truncate the protein in the last two exons and that are not associated with nonsense-mediated decay, although one missense variant has been reported in an affected proband (PMID: 39033379). This gene-disease relationship is also supported by experimental evidence (expression-level evidence, functional alteration evidence, mouse model; PMID: 19449316, 33763417). Expression-level evidence shows high expression in the hippocampus, especially in the dentate gyrus. Functional alteration analysis supports that *KIDINS220* impairs adipocyte differentiation. A mouse model shows that mutating *KIDINS220* reduces dendritic complexity and increases spine elimination. This gene-disease pair was originally evaluated by the Cerebral Palsy GCEP on September 16, 2024 (SOP Version 11). It was re-evaluated on July 2, 2026 (SOP Version 12). As a result of this reevaluation, the classification increased from moderate to definitive with the addition of new genetic evidence (PMIDs: 39033379, 39336781). This gene-disease relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

ventriculomegaly and arthrogryposisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859184

Submitter: G2P

spastic paraplegia, intellectual disability, nystagmus, and obesitySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0015007

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Spastic paraplegia, intellectual disability, nystagmus, and obesity (SINO); Ventriculomegaly and arthrogryposisAR

Manifestation: Cardiovascular; Craniofacial; Endocrine; Musculoskeletal; Neurologic; Ophthalmologic

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

Refs: 27005418; 28934391; 32909676; 33205811

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KIDINS220 variants in ClinVar

14 Conditions Cataloged

not providedTotal: 803

KIDINS220-related disorderTotal: 655

Inborn genetic diseasesTotal: 202

Spastic paraplegia, intellectual disability, nystagmus, and obesityTotal: 75

not specifiedTotal: 68

Ventriculomegaly and arthrogryposisTotal: 33

Early onset severe obesityTotal: 6

Intellectual disabilityTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020738.4. 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			8 clinvar	298 clinvar	6 clinvar	312
missense			661 clinvar	54 clinvar	3 clinvar	718
nonsense	10 clinvar	17 clinvar	8 clinvar			35
start loss						0
frameshift	14 clinvar	25 clinvar	12 clinvar			51
splice donor/acceptor (+/-2bp)		4 clinvar	19 clinvar	2 clinvar		25
Total	24	46	708	354	9	1141

Highest pathogenic variant AF is 0.000015488873

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 72 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020738.4	RefSeq	NP_065789.1	29	MANE Select
ENST00000256707.8	Ensembl	ENSP00000256707.4	29	MANE Select
NM_001348729.2	RefSeq	NP_001335658.1	29	Standard
NM_001348731.2	RefSeq	NP_001335660.1	28	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Neurotrophin signaling pathway - Homo sapiens (human)
Brain-Derived Neurotrophic Factor (BDNF) signaling pathway
Signal Transduction
ARMS-mediated activation
Prolonged ERK activation events

Biological Process

activation of MAPKK activity
in utero embryonic development
positive regulation of neuron projection development
nerve growth factor signaling pathway
dendrite morphogenesis

Molecular Function

protein kinase regulator activity
PDZ domain binding

Cellular Component

late endosome
cytosol
membrane
integral component of membrane
protein-containing complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000256707
Coding exons: 29
Length: 112353
Individuals with no LoFs: 124725
Homozygous LoFs: 0
Heterozygous LoFs: 70
Defined: 124795
p: 0.000280

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.26	780	979	0.797	0.0000528	11608
Missense (PolyPhen)		271	419.05	0.6467		5196
Synonymous	0.222	362	367	0.985	0.0000213	3451
Loss of Function	6.41	20	83.0	0.241	0.00000444	1018

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0017	0.0017	notable
Latino/Admixed American	0.00026	0.00023	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00029	0.00028	rare
Finnish	0.000048	0.000046	rare
European (Non-Finnish)	0.00022	0.00022	rare
South Asian	0.00013	0.00013	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Promotes a prolonged MAP-kinase signaling by neurotrophins through activation of a Rap1-dependent mechanism. Provides a docking site for the CRKL-C3G complex, resulting in Rap1-dependent sustained ERK activation. May play an important role in regulating postsynaptic signal transduction through the syntrophin-mediated localization of receptor tyrosine kinases such as EPHA4. In cooperation with SNTA1 can enhance EPHA4-induced JAK/STAT activation. Plays a role in nerve growth factor (NGF)- induced recruitment of RAPGEF2 to late endosomes and neurite outgrowth. May play a role in neurotrophin- and ephrin-mediated neuronal outgrowth and in axon guidance during neural development and in neuronal regeneration (By similarity). Modulates stress- induced apoptosis of melanoma cells via regulation of the MEK/ERK signaling pathway. {ECO:0000250, ECO:0000269|PubMed:18089783}.;
Disease: DISEASE: Spastic paraplegia, intellectual disability, nystagmus, and obesity (SINO) [MIM:617296]: An autosomal dominant syndrome characterized by rapid growth in infancy, obesity, global developmental delay, intellectual disability, spastic paraplegia, ocular defects, and dysmorphic facial features. {ECO:0000269|PubMed:27005418}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.588

Intolerance Scores

LoFtool: 0.623
RVIS EVS: -2.25
RVIS percentile EVS: 1.3

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.905

Gene Damage Prediction

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