RFX6

protein-coding

regulatory factor X6, the group of Regulatory factor X family

Gene summary

The nuclear protein encoded by this gene is a member of the regulatory factor X (RFX) family of transcription factors. Studies in mice suggest that this gene is specifically required for the differentiation of islet cells for the production of insulin, but not for the differentiation of pancreatic polypeptide-producing cells. It regulates the transcription factors involved in beta-cell maturation and function, thus, restricting the expression of the beta-cell differentiation and specification genes. Mutations in this gene are associated with Mitchell-Riley syndrome, which is characterized by neonatal diabetes with pancreatic hypoplasia, duodenal and jejunal atresia, and gall bladder agenesis.[provided by RefSeq, Sep 2010]

Previous symbols:

RFXDC1

MANE transcript

NM_173560.4

Inheritance

SD, AR, AD

ClinVar variants

P:51U:159B:90

Top phenotype

Mitchell-Riley syndrome

gnomAD constraint

pLI —, LoF o/e 0.31

Max pathogenic AF

—

Genomic locus

chr6:116,877,212-116,932,161

External References & Databases

Ensembl (ENSG00000185002)

Transcript & Mutation Effects

hg38 • Region Span ~54.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hypoplastic pancreas-intestinal atresia-hypoplastic gallbalder syndromeSTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0017400

Submitter: PanelApp Australia

hypoplastic pancreas-intestinal atresia-hypoplastic gallbalder syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0017400

Submitter: Labcorp Genetics (formerly Invitae)

Mitchell-Riley syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014315

Submitter: Genomics England PanelApp

hypoplastic pancreas-intestinal atresia-hypoplastic gallbalder syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017400

Submitter: Orphanet

Martinez-Frias syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011042

Submitter: G2P

monogenic diabetesDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015967

Submitter: ClinGen

Since 2004, RFX6 has been associated with Mitchell-Riley syndrome, an autosomal recessive genetic disorder characterized by neonatal diabetes, pancreatic hypoplasia, intestinal atresia, and gallbladder aplasia or hypoplasia (OMIM #615710). In 2017, truncation variants in RFX6 were first reported to cause autosomal dominant monogenic diabetes with reduced penetrance (PMID: 29026101). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism between the two disorders but observed a difference in inheritance patterns, phenotypic variability, and variant spectrum. Therefore, the curation has been been split into two disease entities The evidence for MItchell-Riley syndrome is being curated separately. The evidence for the split curation for RFX6-related monogenic diabetes is as follows: The seven variants (one missense, five nonsense, and one frameshift) that have been reported in seven probands in six publications (PMIDs:27185633, 29026101, 31001871, 33721395, 34416793, 34387403) are included in this curation. It should be noted that all variants except one implicated in autosomal dominant monogenic diabetes have been truncation variants. The missense variant segregated with several affected family members in one family, but no functional assays were reported, so it cannot be ruled out that it was tracking an unknown causal regulatory variant. Thus, at present non-truncation variants should be interpreted with caution. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is reported to be heterozygous loss of function variants in the RFX6 gene as responsible for monogenic diabetes. This gene-disease relationship is supported by transcriptional activation assay and subcellular localization assay in HEK293 cells and mouse conditional knockout models (PMIDs: 33721395, 25497096, 3 points). In summary, there is definitive evidence supporting the relationship between RFX6 and autosomal dominant inheritance of monogenic diabetes. 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 Monogenic diabetes expert panel GCEP on the meeting date March 20, 2024 (SOP Version [#9].)

Clinical Genomic Database (CGD)

Mitchell-Riley syndromeAR

Manifestation: Endocrine; Gastrointestinal

Intervention: Endocrine; Gastrointestinal

Rationale: While the condition may be recognizable, prompt treatment of gastrointestinal (including pancreatic) issues would be beneficical

Refs: 10528254; 15592663; 18512226; 19887127; 20148032; 21965172; 22662242; 23914949; 26264437

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RFX6 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 242

Inborn genetic diseasesTotal: 75

RFX6-related disorderTotal: 73

Hypoplastic pancreas-intestinal atresia-hypoplastic gallbalder syndromeTotal: 41

not specifiedTotal: 34

Monogenic diabetesTotal: 17

Maturity-onset diabetes of the youngTotal: 2

Syndromic Monogenic DiabetesTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_173560.4. 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			2 clinvar	60 clinvar	2 clinvar	64
missense		5 clinvar	153 clinvar	27 clinvar	1 clinvar	186
nonsense	8 clinvar	9 clinvar	3 clinvar			20
start loss						0
frameshift	10 clinvar	11 clinvar	1 clinvar			22
splice donor/acceptor (+/-2bp)	4 clinvar	4 clinvar				8
Total	22	29	159	87	3	300

Highest pathogenic variant AF is 0.00007254986

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_173560.4	RefSeq	NP_775831.2	19	MANE Select
ENST00000332958.3	Ensembl	ENSP00000332208.2	19	MANE Select
ENST00001137917.1	Ensembl	ENSP00000807355.1	19	Standard
XM_011535589.2	RefSeq	XP_011533891.1	18	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
rfx6	Danio rerio	Structure: endocrine pancreas Quality: undifferentiated abnormal

Gene / Model

Organism

Observed Phenotype

rfx6

Danio rerio

Structure: endocrine pancreas

Quality: undifferentiated

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Maturity onset diabetes of the young - Homo sapiens (human)

Biological Process

type B pancreatic cell differentiation
pancreatic A cell differentiation
pancreatic D cell differentiation
regulation of transcription by RNA polymerase II
endocrine pancreas development

Molecular Function

RNA polymerase II regulatory region sequence-specific DNA binding
RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription activator activity, RNA polymerase II-specific
DNA-binding transcription factor activity

Cellular Component

nucleus
nucleolus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000332958
Coding exons: 19
Length: 54952
Individuals with no LoFs: 125672
Homozygous LoFs: 0
Heterozygous LoFs: 76
Defined: 125748
p: 0.000302

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.20	419	494	0.848	0.0000249	6080
Missense (PolyPhen)		87	153.63	0.56628		1891
Synonymous	-0.322	191	185	1.03	0.00000978	1781
Loss of Function	4.56	16	51.2	0.312	0.00000279	587

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.0019	0.0019	notable
European (Non-Finnish)	0.00022	0.00022	rare
South Asian	0.000098	0.000098	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcription factor required to direct islet cell differentiation during endocrine pancreas development. Specifically required for the differentiation of 4 of the 5 islet cell types and for the production of insulin (PubMed:20148032, PubMed:25497100). Not required for pancreatic PP (polypeptide- producing) cells differentiation. Acts downstream of NEUROG3 and regulates the transcription factors involved in beta-cell maturation and function, thereby restricting the expression of the beta-cell differentiation and specification genes, and thus the beta-cell fate choice. Activates transcription by forming a heterodimer with RFX3 and binding to the X-box in the promoter of target genes (PubMed:20148032). Involved in glucose-stimulated insulin secretion by promoting insulin and L-type calcium channel gene transcription (PubMed:25497100). {ECO:0000269|PubMed:20148032, ECO:0000269|PubMed:25497100}.;

Recessive Scores

pRec: 0.105

Intolerance Scores

LoFtool: 0.546
RVIS EVS: 0.2
RVIS percentile EVS: 67.43

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.292

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium