FAT4

protein-coding

FAT atypical cadherin 4, the group of Cadherin related

Gene summary

The protein encoded by this gene is a member of the protocadherin family. This gene may play a role in regulating planar cell polarity (PCP). Studies in mice suggest that loss of PCP signaling may cause cystic kidney disease, and mutations in this gene have been associated with Van Maldergem Syndrome 2. Alternatively spliced transcript variants have been noted for this gene. [provided by RefSeq, Mar 2014]

MANE transcript

NM_001291303.3

Inheritance

ClinVar variants

P:72U:2001B:1310

Top phenotype

Hennekam lymphangiectasia-lymphedema syndrome 2

gnomAD constraint

pLI —, LoF o/e 0.12

Max pathogenic AF

—

Genomic locus

chr4:125,314,918-125,492,932

External References & Databases

Ensembl (ENSG00000196159)

Transcript & Mutation Effects

hg38 • Region Span ~178.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Hennekam lymphangiectasia-lymphedema syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014454

Submitter: Labcorp Genetics (formerly Invitae)

Hennekam syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016256

Submitter: Orphanet

van Maldergem syndrome 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014242

Submitter: G2P

Hennekam lymphangiectasia-lymphedema syndrome 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014454

Submitter: G2P

van Maldergem syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017813

Submitter: Orphanet

FAT4-related neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100603

Submitter: ClinGen

*FAT4* was first reported in relation to FAT4-related neurodevelopmental disorder in 2013 (Cappello S, et al., 2013, PMID: 24056717). It is caused by mutations in the *FAT4* gene, which encodes a protein that is a member of a large family of protocadherins and may play a role in regulating planar cell polarity (PCP) [provided by RefSeq, Mar 2014]. *FAT4* is an endothelial cell protein expressed in lymphatic cells that could alter the trafficking of immune cells out of the circulation, and in some cases resulting in secondary lymphopenia due to losses or third-spacing. Mutations in the *FAT4* gene are implicated in both Hennekam lymphangiectasia-lymphedema syndrome 2 and Van Maldergem syndrome 2, disorders that are characterized by defects in cell adhesion and planar cell polarity. These disorders share overlapping clinical features and are associated with disruptions in planar cell polarity and cadherin-mediated cell adhesion mechanisms. The clinical presentations vary—Hennekam syndrome tends to present with lymphatic dysplasia, while Van Maldergem syndrome 2 is characterized by craniofacial and limb anomalies. Initially regarded as distinct clinical entities, emerging evidence now supports the concept that these disorders represent variable manifestations within a continuum of developmental abnormalities caused by aberrant FAT4 function. (Betterman KL et al., 2020, PMID:32182215). Affected probands may present with brain malformations including hypoplasia of callosal body, hippocampal malrotation, and periventricular nodular heterotopia. Brain anomalies may be underdiagnosed since not all patients are screened for them. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or inheritance pattern between these conditions suggesting that these may constitute a disease spectrum associated with variants in *FAT4*. Therefore, the two conditions– Hennekam lymphangiectasia-lymphedema syndrome 2(OMIM:616006) and Van Maldergem syndrome 2 (OMIM:615546), have been lumped into one disease entity– *FAT4*-related neurodevelopmental disorder. Fourteen variants that have been reported in 11 probands in 3 publications (Cappello S, et al., 2013, PMID: 24056717; Alders M, et al., 2014, PMID: 24913602; Ivanovski I, et al., 2018, PMID: 29681106), are included in this curation. This gene-disease relationship is also supported by a non-human model organism. The shRNA knockdown mouse model demonstrates phenotypes closely resembling those seen in humans with *FAT4*, particularly in the form of neuronal heterotopia, abnormal neuroprogenitor proliferation, and disrupted neuronal migration (Cappello S, et al., 2013, PMID: 24056717). In summary, there is definitive evidence to support the relationship between *FAT4* and autosomal recessive *FAT4*-related neurodevelopmental disorder. 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 Severe Combined Immune Deficiency (SCID) and Combined Immune Deficiency (CID) GCEP on the meeting date February 20, 2025 (SOP Version 11).

multiple congenital anomalies/dysmorphic syndrome-intellectual disabilitySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0015159

Submitter: Ambry Genetics

FAT4-related neurodevelopmental disorderSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0100603

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Hennekam lymphangiectasia-lymphedema syndrome 2AR

Manifestation: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Craniofacial; Dental; Gastrointestinal; Genitourinary; Musculoskeletal; Neurologic; Pulmonary; Renal

Intervention: Allergy/Immunology/Infectious; Gastrointestinal

Rationale: The condition can include manifestations such as protein-losing enteropathy (which may be refractory), as well as features for which treatment can be beneficial, such as infectious sequelae, for which early and aggressive treatment may be beneficial

Refs: 2624276; 22469822; 22473091; 24056717; 24913602

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FAT4 variants in ClinVar

21 Conditions Cataloged

not providedTotal: 2782

Inborn genetic diseasesTotal: 726

Hennekam lymphangiectasia-lymphedema syndrome 2Total: 617

Van Maldergem syndrome 2Total: 607

not specifiedTotal: 279

FAT4-related disorderTotal: 223

Intellectual disabilityTotal: 5

Hennekam lymphangiectasia-lymphedema syndrome 1Total: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001291303.3. 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	1 clinvar		16 clinvar	1130 clinvar	14 clinvar	1161
missense	3 clinvar	1 clinvar	1970 clinvar	154 clinvar	12 clinvar	2140
nonsense	16 clinvar	11 clinvar	4 clinvar			31
start loss						0
frameshift	22 clinvar	13 clinvar	9 clinvar			44
splice donor/acceptor (+/-2bp)	2 clinvar	3 clinvar	2 clinvar			7
Total	44	28	2001	1284	26	3383

Highest pathogenic variant AF is 0.0000075367657

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001291303.3	RefSeq	NP_001278232.1	17	MANE Select
ENST00000394329.9	Ensembl	ENSP00000377862.4	17	MANE Select
NM_001291285.3	RefSeq	NP_001278214.1	17	Standard
NM_001437895.1	RefSeq	NP_001424824.1	16	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Hippo signaling pathway - multiple species - Homo sapiens (human)

Biological Process

branching involved in ureteric bud morphogenesis
heart morphogenesis
plasma membrane organization
homophilic cell adhesion via plasma membrane adhesion molecules
heterophilic cell-cell adhesion via plasma membrane cell adhesion molecules

Molecular Function

calcium ion binding
protein binding

Cellular Component

plasma membrane
integral component of membrane
apical part of cell
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000394329
Coding exons: 17
Length: 176534
Individuals with no LoFs: 125696
Homozygous LoFs: 0
Heterozygous LoFs: 52
Defined: 125748
p: 0.000207

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.622	2545	2.63e+3	0.966	0.000138	32695
Missense (PolyPhen)		990	1186.1	0.8347		15034
Synonymous	-1.30	1071	1.02e+3	1.05	0.0000556	10185
Loss of Function	9.37	16	132	0.121	0.00000718	1792

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00038	0.00037	rare
Latino/Admixed American	0.000059	0.000058	rare
Ashkenazi Jewish	0.00040	0.00040	rare
East Asian	0.000057	0.000054	rare
Finnish	0.000095	0.000092	rare
European (Non-Finnish)	0.00022	0.00022	rare
South Asian	0.00042	0.00039	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Cadherins are calcium-dependent cell adhesion proteins. FAT4 plays a role in the maintenance of planar cell polarity as well as in inhibition of YAP1-mediated neuroprogenitor cell proliferation and differentiation (By similarity). {ECO:0000250}.;
Disease: DISEASE: Van Maldergem syndrome 2 (VMLDS2) [MIM:615546]: An autosomal recessive disorder characterized by intellectual disability, typical craniofacial features, auditory malformations resulting in hearing loss, and skeletal and limb malformations. Some patients have renal hypoplasia. Brain MRI typically shows periventricular nodular heterotopia. {ECO:0000269|PubMed:24056717}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hennekam lymphangiectasia-lymphedema syndrome 2 (HKLLS2) [MIM:616006]: A form of Hennekam lymphangiectasia-lymphedema syndrome, a generalized lymph-vessels dysplasia characterized by intestinal lymphangiectasia with severe lymphedema of the limbs, genitalia and face. In addition, affected individuals have unusual facies and severe mental retardation. HKLLS2 individuals have lymphangiectasia variably affecting the gut, pericardium, lungs, kidneys, and genitalia. Other features include camptodactyly and rare syndactyly. {ECO:0000269|PubMed:24913602}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.101

Intolerance Scores

LoFtool: 0.323
RVIS EVS: -0.5
RVIS percentile EVS: 21.82

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.731

Gene Damage Prediction

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