WDR72

protein-coding

WD repeat domain 72, the group of WD repeat domain containing

Gene summary

This gene encodes a protein with eight WD-40 repeats. Mutations in this gene have been associated with amelogenesis imperfecta hypomaturation type 2A3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2013]

MANE transcript

NM_182758.4

Inheritance

ClinVar variants

P:53U:264B:25

Top phenotype

Amelogenesis imperfecta, hypomaturation type, IIA3

gnomAD constraint

pLI —, LoF o/e 0.84

Max pathogenic AF

—

Genomic locus

chr15:53,513,741-53,762,878

External References & Databases

Ensembl (ENSG00000166415)

Transcript & Mutation Effects

hg38 • Region Span ~249.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

amelogenesis imperfecta hypomaturation type 2A3MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013181

Submitter: Ambry Genetics

amelogenesis imperfecta type 2SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015048

Submitter: Orphanet

amelogenesis imperfectaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019507

Submitter: ClinGen

The *WDR72* gene is located on chromosome 15 at q21.3 and encodes the WD repeat-containing protein 72. This protein is important in vesicle trafficking in enamel-producing ameloblasts that control the ionic and organic composition of enamel, and is also involved in the localisation of the Ca transporter, SLC24A4 (mutations in which also cause amelogenesis imperfecta) to the ameloblast cell membrane. WDR72 is also expressed in both the proximal and distal tubular cells of the kidneys. *WDR72* mutation was first reported in relation to autosomal recessive amelogenesis imperfecta in 2009 (El-Sayed PMID: 19853237), and in relation to autosomal recessive amelogenesis imperfecta with distal renal tubular acidosis in 2018 (Rungroj PMID:30028003). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in the molecular mechanism or inheritance pattern, and noted phenotypic overlap. Therefore, the following disease entities have been lumped into one disease entity, Amelogenesis imperfecta, type IIA3 (OMIM: 613211) and Amelogenesis imperfecta with distal renal tubular acidosis (no OMIM record). The preferred disease name suggested for this grouping of disorders is ‘Amelogenesis imperfecta with or without distal renal tubular acidosis - *WDR72*’. Many variants have been reported in *WDR72* including mainly null variants, but also missense changes, in many publications and public databases. The maximum score for genetic evidence (12 points) was reached. The mechanism of pathogenicity is loss of function. This gene-disease association is also supported by experimental evidence including expression data and a knockout mouse model. In summary, *WDR72* is definitively associated with Amelogenesis imperfecta with or without distal renal tubular acidosis. This has been demonstrated in both the research and clinical diagnostic setting, and has been upheld over time.

renal tubular acidosisLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0001909

Submitter: Ambry Genetics

amelogenesis imperfecta hypomaturation type 2A3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013181

Submitter: PanelApp Australia

amelogenesis imperfecta hypomaturation type 2A3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013181

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Amelogenesis imperfecta, hypomaturation type, IIA3AR

Manifestation: Dental

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: 19853237; 22243262; 23293580

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to WDR72 variants in ClinVar

10 Conditions Cataloged

Amelogenesis imperfecta hypomaturation type 2A3Total: 221

Inborn genetic diseasesTotal: 155

not providedTotal: 26

WDR72-related disorderTotal: 19

not specifiedTotal: 16

Amelogenesis imperfectaTotal: 6

Renal tubular acidosis, distal, 4, with hemolytic anemiaTotal: 3

Distal renal tubular acidosisTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_182758.4. 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			18 clinvar	9 clinvar		27
missense	1 clinvar	3 clinvar	243 clinvar	15 clinvar	1 clinvar	263
nonsense	4 clinvar	17 clinvar	2 clinvar			23
start loss						0
frameshift	4 clinvar	16 clinvar				20
splice donor/acceptor (+/-2bp)	1 clinvar	7 clinvar	1 clinvar			9
Total	10	43	264	24	1	342

Highest pathogenic variant AF is 0.00007496633

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 39 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_182758.4	RefSeq	NP_877435.3	19	MANE Select
ENST00000360509.10	Ensembl	ENSP00000353699.5	19	MANE Select
NM_001277176.2	RefSeq	NP_001264105.1	3	Standard
ENST00000396328.5	Ensembl	ENSP00000379619.1	19	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

enamel mineralization

Cellular Component

cytoplasm
endosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000396328
Coding exons: 19
Length: 249138
Individuals with no LoFs: 125562
Homozygous LoFs: 0
Heterozygous LoFs: 186
Defined: 125748
p: 0.000740

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.956	617	554	1.11	0.0000259	7231
Missense (PolyPhen)		166	165.41	1.0036		2255
Synonymous	-0.485	206	197	1.04	0.00000968	2075
Loss of Function	1.10	46	54.8	0.840	0.00000274	699

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00068	0.00068	rare
Latino/Admixed American	0.00064	0.00064	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00093	0.00092	rare
Finnish	0.00060	0.00060	rare
European (Non-Finnish)	0.00086	0.00085	rare
South Asian	0.00069	0.00069	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a major role in formation of tooth enamel (PubMed:19853237, PubMed:25008349). Specifically required during the maturation phase of amelogenesis for normal formation of the enamel matrix and clearance of enamel proteins. May be involved in localization of the calcium transporter SLC24A4 to the ameloblast cell membrane. {ECO:0000250|UniProtKB:D3YYM4, ECO:0000269|PubMed:19853237, ECO:0000269|PubMed:25008349}.;
Disease: DISEASE: Amelogenesis imperfecta, hypomaturation type, 2A3 (AI2A3) [MIM:613211]: A defect of enamel formation. The disorder involves both primary and secondary dentitions. The teeth have a shiny agar jelly appearance and the enamel is softer than normal. Brown pigment is present in middle layers of enamel. {ECO:0000269|PubMed:19853237, ECO:0000269|PubMed:25008349}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0874

Intolerance Scores

LoFtool: 0.979
RVIS EVS: -0.01
RVIS percentile EVS: 52.35

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

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