HYDIN

protein-coding

HYDIN axonemal central pair apparatus protein, the group of Protein phosphatase 1 regulatory subunits

Gene summary

This gene encodes a protein that may be involved in cilia motility. Mutations in this gene cause of autosomal recessive primary ciliary dyskinesia-5, a disorder characterized by the accumulation of cerebrospinal fluid within the ventricles of the brain. A duplicate copy of this gene has been found in humans on chromosome 1. [provided by RefSeq, Jan 2013]

MANE transcript

NM_001270974.2

Inheritance

AR, AD

ClinVar variants

P:98U:379B:320

Top phenotype

Ciliary dyskinesia, primary, 5

gnomAD constraint

pLI —, LoF o/e 0.42

Max pathogenic AF

—

Genomic locus

chr16:70,802,084-71,230,722

External References & Databases

Ensembl (ENSG00000157423)

Transcript & Mutation Effects

hg38 • Region Span ~428.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

primary ciliary dyskinesia 5MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012088

Submitter: Ambry Genetics

primary ciliary dyskinesia 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012088

Submitter: Labcorp Genetics (formerly Invitae)

primary ciliary dyskinesia 5DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012088

Submitter: G2P

primary ciliary dyskinesia 5DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012088

Submitter: ClinGen

Primary ciliary dyskinesia (PCD) is a clinically and genetically heterogeneous group of diseases resulting from variants in genes involved in the transport, assembly, and function of motile cilia (PMID 33304404). The HYDIN gene was first reported to cause PCD5 in humans in 2012 (PMID 23022101). Major parts of the gene are duplicated in the HYDIN2 pseudogene which might confound genetic diagnosis. Ciliary defects of the respiratory epithelium in the reported patients result in otitis media, sinusitis, recurrent chest infection and progressive airway destruction. Male infertility due to dysfunctional sperm tails is also reported (PMID 23022101). Absence of the situs inversus phenotype characteristic of other forms of PCD reflects the underlying defect in central pair (CP) apparatus, which is considered irrelevant to the nodal cilium that establishes the left-right body asymmetry (PMID 31545650). Deficiency of the CP-apparatus-associated protein HYDIN results in lack of the C2b projection of the central pair with reduced beating amplitudes of respiratory cilia and stiff sperm flagella (PMID 23022101). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found the molecular mechanism and autosomal recessive mode of inheritance to be consistent among unrelated patients, while the phenotypic variability among them appeared to represent a spectrum of disease rather than separate disease entities. Therefore, the asserted disease associated with HYDIN variants, primary ciliary dyskinesia 5 (MONDO:0012088), was curated as a single entity. Ten splice site, nonsense and frameshift variants were reported in 5 publications (PMIDS 23022101, 23849777, 31089940, 31545650, 26139845). The disease consistently segregates in 1 German and 3 Faroe Islander families, and provides a scorable genetic evidence for segregation analysis of the autosomal recessive disease (PMID 23022101). Experimental evidence also supports this gene disease association. HYDIN expression in ciliated epithelial tissues relevant to PCD was identified in multiple papers (PMIDs 23715323, 12719380). The biochemical function of HYDIN protein in the axonemal central pair and its functional alteration in patient cells are consistent with a critical role in motile cilia structure and function (PMID 23022101). Abnormal ciliary structure and function were also evident in Hydin mutant mice (PMID 18250199). Similarly, Hydin knockdown causes flagellar paralysis in Chlamydomonas (PMID 17296796). In summary, HYDIN is definitively associated with autosomal recessive primary ciliary dyskinesia 5. This has been repeatedly demonstrated in both research and diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Motile Ciliopathy GCEP on February 10th, 2022 (SOP Version 8).

primary ciliary dyskinesia 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012088

Submitter: PanelApp Australia

primary ciliary dyskinesiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016575

Submitter: Orphanet

Clinical Genomic Database (CGD)

Ciliary dyskinesia, primary, 5AR

Manifestation: Allergy/Immunology/Infectious; Gastrointestinal; Pulmonary

Intervention: Allergy/Immunology/Infectious; Pulmonary

Rationale: Pulmonary surveillance may be beneficial to assess respiratory function and institute early management measures; In order to facilitate mucus clearance, aggressive interventions (eg, chest percussion and oscillatory vest), as well as vaccinations and early and aggressive treatment of respiratory infections may be beneficial

Refs: 14985390; 23022101; 23849777

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HYDIN variants in ClinVar

14 Conditions Cataloged

not providedTotal: 354

not specifiedTotal: 280

Inborn genetic diseasesTotal: 201

Primary ciliary dyskinesia 5Total: 131

HYDIN-related disordersTotal: 20

HYDIN-related disorderTotal: 8

Primary ciliary dyskinesiaTotal: 6

Respiratory ciliopathies including non-CF bronchiectasisTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001270974.2. 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	219 clinvar	1 clinvar	228
missense	1 clinvar	3 clinvar	358 clinvar	96 clinvar	2 clinvar	460
nonsense	11 clinvar	28 clinvar	2 clinvar			41
start loss						0
frameshift	8 clinvar	26 clinvar	3 clinvar	2 clinvar		39
splice donor/acceptor (+/-2bp)	6 clinvar	15 clinvar	8 clinvar			29
Total	26	72	379	317	3	797

Highest pathogenic variant AF is 0.00015243015

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 23 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001270974.2	RefSeq	NP_001257903.1	85	MANE Select
ENST00000393567.7	Ensembl	ENSP00000377197.2	85	MANE Select
NM_001198542.1	RefSeq	NP_001185471.1	19	Standard
NM_001198543.1	RefSeq	NP_001185472.1	19	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

epithelial cell development
cilium movement
ventricular system development
trachea development
axonemal central apparatus assembly

Cellular Component

axonemal central pair projection

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000393567
Coding exons: 85
Length: 423345
Individuals with no LoFs: 125524
Homozygous LoFs: 0
Heterozygous LoFs: 224
Defined: 125748
p: 0.000891

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.810	1990	2.09e+3	0.950	0.000117	33454
Missense (PolyPhen)		709	809.39	0.87597		12630
Synonymous	-0.966	853	818	1.04	0.0000486	9768
Loss of Function	7.14	72	173	0.415	0.00000935	2805

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00084	0.00080	rare
Latino/Admixed American	0.00041	0.00040	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00018	0.00016	rare
Finnish	0.0047	0.0046	notable
European (Non-Finnish)	0.00069	0.00066	rare
South Asian	0.00050	0.00049	rare
Other	0.00052	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for ciliary motility. {ECO:0000250}.;
Disease: DISEASE: Ciliary dyskinesia, primary, 5 (CILD5) [MIM:608647]: An autosomal recessive form of primary dyskinesia, a disorder characterized by abnormalities of motile cilia. Respiratory infections leading to chronic inflammation and bronchiectasis are recurrent, due to defects in the respiratory cilia; reduced fertility is often observed in male patients due to abnormalities of sperm tails. Half of the patients exhibit randomization of left-right body asymmetry and situs inversus, due to dysfunction of monocilia at the embryonic node. Primary ciliary dyskinesia associated with situs inversus is referred to as Kartagener syndrome. CILD5 is characterized by early onset of a progressive decline in lung function due to an inability to clear mucus and particles from the airways. Affected individuals have recurrent infections of the sinuses, ears, airways, and lungs. Sperm motility is also decreased. Individuals with CILD5 do not have situs inversus. {ECO:0000269|PubMed:23022101, ECO:0000269|PubMed:25186273}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.106

Gene Damage Prediction

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