CDAN1

protein-coding

codanin 1

Gene summary

This gene encodes a protein that appears to play a role in nuclear envelope integrity, possibly related to microtubule attachments. Mutations in this gene cause congenital dyserythropoietic anemia type I, a disease resulting in morphological and functional abnormalities of erythropoiesis. [provided by RefSeq, Jul 2009]

MANE transcript

NM_138477.4

Inheritance

ClinVar variants

P:78U:395B:228

Top phenotype

Anemia, dyserythropoietic congenital, type Ia

gnomAD constraint

pLI —, LoF o/e 0.5

Max pathogenic AF

—

Genomic locus

chr15:42,723,544-42,737,128

External References & Databases

Ensembl (ENSG00000140326)

Transcript & Mutation Effects

hg38 • Region Span ~13.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

anemia, congenital dyserythropoietic, type 1aDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009135

Submitter: ClinGen

Codanin 1 (CDAN1; MIM# 224120), also known as Discs Lost Homolog or DLT, is a negative regulator of chromatin replication and plays an important role in erythropoiesis. CDAN1 is a gene associated with autosomal recessive congenital dyserythropoietic anemia type 1a (CDA1, AR; MIM# 224120). The molecular etiology of CDA1 was first described by Dgany, et al in 2002 [PMID:12434312] and has been described in many affected individuals since [PMID:29599085, 29668551, 34782754, 29031773, 24196372, 31900952, 35012925, 16098079, 33401150, 30786798]. Variants are nonsense, frameshift, and missense. Loss-of-function is the proposed mechanism of disease, however no homozygous or compound het null variants have been identified in humans and complete knockout is early embryonic lethal in mice [PMID:34234691], suggesting that some residual function is required. Additionally, many missense variants identified in affected individuals have not been functionally evaluated for presumed partial loss-of-function. Distinctive erythroblast abnormalities are considered pathognomonic for CDA1, including spongy heterochromatin, internuclear chromatin bridges, and invaginated nuclear pores [PMID:30836435]. CDA1 is often diagnosed in childhood, but a fetal sub-type presents with hemolytic anemia and additional variable features including hydrops fetalis, small for gestational age, hepatosplenomegaly, pulmonary hypertension, neonatal jaundice, and occasional distal limb abnormalities such as toe syndactyly and nail hypoplasia [PMID: 20301759]. Genetic evidence for congenital dyserythropoietic anemia type 1a was scored at the maximum of 12 points. Functional evidence including mouse and zebrafish models recapitulating the observed human phenotype and biochemical function [PMID: 34234691] were scored for an additional 2.5 points. Given this and its replication in the literature over time, the association with the CDAN1 gene and congenital dyserythropoietic anemia type 1a is curated as Definitive by the Prenatal Gene Curation Expert Panel.

congenital dyserythropoietic anemia type 1SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0020337

Submitter: Orphanet

anemia, congenital dyserythropoietic, type 1aSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009135

Submitter: Labcorp Genetics (formerly Invitae)

anemia, congenital dyserythropoietic, type 1aDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009135

Submitter: Ambry Genetics

congenital dyserythropoietic anemiaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019403

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Anemia, dyserythropoietic congenital, type IaAR

Manifestation: Cardiovascular; Hematologic; Musculoskeletal; Renal

Intervention: Hematologic

Rationale: Individuals may require RBC transfusions in the neonatal period; Medical therapy (eg, with alpha-interferon) may be beneficial; Iron overload is common

Refs: 718245; 476312; 3096054; 2757972; 2124499; 7725852; 10971401; 10753260; 12434312; 16098079; 16141353; 18824595; 21378561; 21364188; 22504250

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CDAN1 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 577

Anemia, congenital dyserythropoietic, type 1aTotal: 262

Inborn genetic diseasesTotal: 200

Congenital dyserythropoietic anemia, type ITotal: 121

not specifiedTotal: 99

CDAN1-related disorderTotal: 64

Congenital anemiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_138477.4. 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			9 clinvar	193 clinvar	6 clinvar	208
missense	3 clinvar	13 clinvar	379 clinvar	28 clinvar	1 clinvar	424
nonsense	8 clinvar	7 clinvar	1 clinvar			16
start loss						0
frameshift	20 clinvar	16 clinvar	2 clinvar			38
splice donor/acceptor (+/-2bp)	2 clinvar	9 clinvar	4 clinvar			15
Total	33	45	395	221	7	701

Highest pathogenic variant AF is 0.00029346184

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 24 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_138477.4	RefSeq	NP_612486.2	28	MANE Select
ENST00000356231.4	Ensembl	ENSP00000348564.3	28	MANE Select
ENST00000562465.5	Ensembl	ENSP00000454246.1	11	Standard
ENST00000563260.1	Ensembl	ENSP00000455536.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

chromatin organization
protein localization
negative regulation of DNA replication
chromatin assembly

Molecular Function

protein binding

Cellular Component

nucleus
cytoplasm
cytosol
plasma membrane
endomembrane system

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000356231
Coding exons: 28
Length: 13568
Individuals with no LoFs: 125648
Homozygous LoFs: 0
Heterozygous LoFs: 100
Defined: 125748
p: 0.000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.937	716	649	1.10	0.0000398	7775
Missense (PolyPhen)		384	375.43	1.0228		4588
Synonymous	-3.06	339	274	1.24	0.0000158	2645
Loss of Function	3.61	30	60.2	0.498	0.00000332	669

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.00032	0.00032	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00027	0.00027	rare
Finnish	0.00042	0.00042	rare
European (Non-Finnish)	0.00046	0.00042	rare
South Asian	0.00036	0.00036	rare
Other	0.0013	0.0013	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May act as a negative regulator of ASF1 in chromatin assembly. {ECO:0000269|PubMed:22407294}.;

Recessive Scores

pRec: 0.184

Intolerance Scores

LoFtool: 0.0662
RVIS EVS: -0.83
RVIS percentile EVS: 11.54

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): K
Indispensability pred.: N
Indispensability score: 0.362

Gene Damage Prediction

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