Au-Kline syndrome

Summary

Au-Kline syndrome (MONDO:0014700) is a disease caused by HNRNPK (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: HNRNPK (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 86

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Au-Kline syndrome
Mondo ID	MONDO:0014700
MeSH	C565736
OMIM	604916, 616580
Orphanet	2729, 453504
SNOMED CT	722065002
UMLS	C4225274
MedGen	900671
GARD	0004064
Is cancer (heuristic)	no

Also known as: Au-Kline syndrome · AUKS · congenital hydronephrosis with cleft palate, characteristic facies, hypotonia, and intellectual disability · congenital hydronephrosis with cleft palate, characteristic facies, hypotonia, and mental retardation · hydronephrosis, congenital, with cleft palate, characteristic facies, hypotonia, and intellectual disability · hydronephrosis, congenital, with cleft palate, characteristic facies, hypotonia, and mental retardation · neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome due to a point mutation · Okamoto syndrome

Data availability: 86 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome › Au-Kline syndrome

Related subtypes (1): neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome due to 9q21 microdeletion

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

86 retrieved; paginated sample, class counts are floors:

31 likely pathogenic, 24 pathogenic, 23 uncertain significance, 4 pathogenic/likely pathogenic, 4 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1029561	NM_031263.4(HNRNPK):c.573_574del (p.Arg191fs)	HNRNPK	Pathogenic	criteria provided, single submitter
1685880	NM_031263.4(HNRNPK):c.1240C>T (p.Arg414Cys)	HNRNPK	Pathogenic	criteria provided, single submitter
1706529	NM_031263.4(HNRNPK):c.1040_1041del (p.Ser347fs)	HNRNPK	Pathogenic	criteria provided, single submitter
1706586	NM_031263.4(HNRNPK):c.402+1G>A	HNRNPK	Pathogenic	criteria provided, single submitter
1708495	NM_031263.4(HNRNPK):c.1048_1051del (p.Asp350fs)	HNRNPK	Pathogenic	criteria provided, single submitter
1803038	NM_031263.4(HNRNPK):c.1192-7_1192-3del	HNRNPK	Pathogenic	criteria provided, single submitter
1805748	NM_031263.4(HNRNPK):c.440T>A (p.Leu147Ter)	HNRNPK	Pathogenic	criteria provided, single submitter
212775	NM_031263.4(HNRNPK):c.953+1dup	HNRNPK	Pathogenic	criteria provided, single submitter
221225	NM_031263.4(HNRNPK):c.931_932insTT (p.Pro311fs)	HNRNPK	Pathogenic	criteria provided, single submitter
2444445	NM_031263.4(HNRNPK):c.886C>T (p.Arg296Ter)	HNRNPK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2501876	NM_031263.4(HNRNPK):c.1108+1G>T	HNRNPK	Pathogenic	criteria provided, multiple submitters, no conflicts
2573160	NM_031263.4(HNRNPK):c.1361+1G>A	HNRNPK	Pathogenic	no assertion criteria provided
2573161	NM_031263.4(HNRNPK):c.257+5G>A	HNRNPK	Pathogenic	no assertion criteria provided
280639	NM_031263.4(HNRNPK):c.779dup (p.Phe261_Asp262insTer)	HNRNPK	Pathogenic	criteria provided, multiple submitters, no conflicts
3238832	NM_031263.4(HNRNPK):c.1093-2A>C	HNRNPK	Pathogenic	criteria provided, single submitter
3254786	NM_031263.4(HNRNPK):c.1122_1123insT (p.Gly375fs)	HNRNPK	Pathogenic	criteria provided, single submitter
3764099	NM_031263.4(HNRNPK):c.1074dup (p.Met359fs)	HNRNPK	Pathogenic	criteria provided, single submitter
3766482	NM_031263.4(HNRNPK):c.136C>T (p.Arg46Cys)	HNRNPK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3899365	NM_031263.4(HNRNPK):c.504_507del (p.Lys168fs)	HNRNPK	Pathogenic	criteria provided, single submitter
449308	NM_031263.4(HNRNPK):c.1008+1G>A	HNRNPK	Pathogenic	criteria provided, multiple submitters, no conflicts
503601	NM_031263.4(HNRNPK):c.998dup (p.Tyr333Ter)	HNRNPK	Pathogenic	criteria provided, multiple submitters, no conflicts
503602	NM_002140.4(HNRNPK):c.1009delG	HNRNPK	Pathogenic	criteria provided, single submitter
503603	NM_031263.4(HNRNPK):c.859C>T (p.Arg287Ter)	HNRNPK	Pathogenic	criteria provided, multiple submitters, no conflicts
503604	NM_002140.4(HNRNPK):c.1094delG	HNRNPK	Pathogenic	criteria provided, single submitter
625163	NM_031263.4(HNRNPK):c.464T>C (p.Leu155Pro)	HNRNPK	Pathogenic	criteria provided, single submitter
818201	NM_031263.4(HNRNPK):c.673T>C (p.Tyr225His)	HNRNPK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
931166	NM_031263.4(HNRNPK):c.1192-14_1192-2del	HNRNPK	Pathogenic	criteria provided, single submitter
212776	NM_031263.4(HNRNPK):c.257G>A (p.Arg86His)	HNRNPK-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1029562	NM_031263.4(HNRNPK):c.645+1G>T	HNRNPK	Likely pathogenic	criteria provided, single submitter
1077160	NM_031263.4(HNRNPK):c.1282G>A (p.Glu428Lys)	HNRNPK	Likely pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
HNRNPK	Definitive	Autosomal dominant	Au-Kline syndrome	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HNRNPK	Orphanet:352665	Neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-skeletal anomalies syndrome due to 9q21.3 microdeletion
HNRNPK	Orphanet:453504	Neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-skeletal anomalies syndrome due to a point mutation
ATP7A	Orphanet:139557	X-linked distal spinal muscular atrophy type 3
ATP7A	Orphanet:198	Occipital horn syndrome
ATP7A	Orphanet:388	Hirschsprung disease
ATP7A	Orphanet:565	Menkes disease

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HNRNPK	HGNC:5044	ENSG00000165119	P61978	Heterogeneous nuclear ribonucleoprotein K	gencc,clinvar
HNRNPK-AS1	HGNC:56061	ENSG00000235298		HNRNPK antisense RNA 1	clinvar
ATP7A	HGNC:869	ENSG00000165240	Q04656	Copper-transporting ATPase 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HNRNPK	Heterogeneous nuclear ribonucleoprotein K	One of the major pre-mRNA-binding proteins.
ATP7A	Copper-transporting ATPase 1	ATP-driven copper (Cu(+)) ion pump that plays an important role in intracellular copper ion homeostasis.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transcription factor	1	2.8×	0.587
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HNRNPK	Other/Unknown	no		KH_dom, KH_dom_type_1, ROK_N
HNRNPK-AS1	Other/Unknown	no
ATP7A	Transcription factor	no	7.2.2.8	P_typ_ATPase, HMA_dom, HMA_Cu_ion-bd

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
ganglionic eminence	1
ventricular zone	1
endometrium	1
left lobe of thyroid gland	1
right uterine tube	1
buccal mucosa cell	1
trabecular bone tissue	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HNRNPK	167	ubiquitous	marker	ventricular zone, calcaneal tendon, ganglionic eminence
HNRNPK-AS1	132		marker	endometrium, right uterine tube, left lobe of thyroid gland
ATP7A	275	ubiquitous	marker	buccal mucosa cell, trabecular bone tissue, upper leg skin

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HNRNPK	5,582
ATP7A	3,901
HNRNPK-AS1	0

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATP7A	Q04656	22
HNRNPK	P61978	9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 3 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Ion influx/efflux at host-pathogen interface	1	1427.5×	0.012	ATP7A
Detoxification of Reactive Oxygen Species	1	150.3×	0.033	ATP7A
SUMOylation of RNA binding proteins	1	119.0×	0.033	HNRNPK
Antimicrobial peptides	1	112.0×	0.033	ATP7A
Ion transport by P-type ATPases	1	103.8×	0.033	ATP7A
Cellular response to chemical stress	1	71.4×	0.040	ATP7A
HCMV Late Events	1	49.2×	0.041	HNRNPK
Ion channel transport	1	48.0×	0.041	ATP7A
mRNA Polyadenylation	1	43.9×	0.041	HNRNPK
Processing of Capped Intron-Containing Pre-mRNA	1	41.1×	0.041	HNRNPK
mRNA Splicing - Major Pathway	1	27.3×	0.056	HNRNPK
Dengue Virus-Host Interactions	1	22.8×	0.061	HNRNPK
Cellular responses to stress	1	18.4×	0.070	ATP7A
Cellular responses to stimuli	1	15.7×	0.076	ATP7A
Innate Immune System	1	12.8×	0.083	ATP7A
Transport of small molecules	1	12.6×	0.083	ATP7A
Immune System	1	6.5×	0.148	ATP7A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator	1	8426.0×	0.003	HNRNPK
obsolete negative regulation of catecholamine metabolic process	1	4213.0×	0.003	ATP7A
obsolete L-tryptophan metabolic process	1	2808.7×	0.003	ATP7A
epinephrine metabolic process	1	2808.7×	0.003	ATP7A
copper ion export	1	2808.7×	0.003	ATP7A
obsolete tyrosine metabolic process	1	2106.5×	0.003	ATP7A
catecholamine metabolic process	1	2106.5×	0.003	ATP7A
positive regulation of low-density lipoprotein particle clearance	1	2106.5×	0.003	HNRNPK
T-helper cell differentiation	1	1685.2×	0.004	ATP7A
copper ion import	1	1203.7×	0.004	ATP7A
pyramidal neuron development	1	1053.2×	0.004	ATP7A
norepinephrine biosynthetic process	1	1053.2×	0.004	ATP7A
regulatory ncRNA-mediated heterochromatin formation	1	936.2×	0.004	HNRNPK
copper ion transport	1	842.6×	0.004	ATP7A
serotonin metabolic process	1	842.6×	0.004	ATP7A
norepinephrine metabolic process	1	766.0×	0.004	ATP7A
elastic fiber assembly	1	766.0×	0.004	ATP7A
positive regulation of melanin biosynthetic process	1	702.2×	0.004	ATP7A
regulation of oxidative phosphorylation	1	601.9×	0.005	ATP7A
detoxification of copper ion	1	561.7×	0.005	ATP7A
removal of superoxide radicals	1	526.6×	0.005	ATP7A
cerebellar Purkinje cell differentiation	1	526.6×	0.005	ATP7A
dopamine metabolic process	1	495.6×	0.005	ATP7A
intracellular copper ion homeostasis	1	468.1×	0.005	ATP7A
random inactivation of X chromosome	1	468.1×	0.005	HNRNPK
regulation of mRNA splicing, via spliceosome	1	443.5×	0.005	HNRNPK
central nervous system neuron development	1	401.2×	0.005	ATP7A
negative regulation of mRNA splicing, via spliceosome	1	383.0×	0.005	HNRNPK
release of cytochrome c from mitochondria	1	351.1×	0.005	ATP7A
pigmentation	1	351.1×	0.005	ATP7A

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HNRNPK	0	0
HNRNPK-AS1	0	0
ATP7A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ATP7A	11	Binding:11
HNRNPK	7	Binding:7

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ATP7A	7.2.2.8, 7.2.2.9	P-type Cu+ transporter, P-type Cu2+ transporter

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	HNRNPK, HNRNPK-AS1, ATP7A

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
HNRNPK	7	—
HNRNPK-AS1	0	—
ATP7A	11	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.