IL1RAPL1

  • 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
IL1RAPL1 (HGNC:5996) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
interleukin 1 receptor accessory protein like 1
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
IL1RAPL, MRX34, MRX21, MRX10
Alias symbols
OPHN4, TIGIRR-2, IL1R8, IL1RAPL-1
%HI
1.75(Read more about the DECIPHER Haploinsufficiency Index)
pLI
1(Read more about gnomAD pLI score)
LOEUF
0.2(Read more about gnomAD LOEUF score)
Cytoband
Xp21.3-p21.2
Genomic Coordinates
GRCh37/hg19: chrX:28605563-29974835 NCBI Ensembl UCSC
GRCh38/hg38: chrX:28587446-29956718 NCBI Ensembl UCSC
MANE Select Transcript
NM_014271.4 ENST00000378993.6 (Read more about MANE Select)
Function
May regulate secretion and presynaptic differentiation through inhibition of the activity of N-type voltage-gated calcium channel (PubMed:12783849). May activate the MAP kinase JNK (PubMed:15123616). Plays a role in neurite outgrowth (By similarity). During dendritic spine formation can bidirectionally induce pre- and post-synaptic differentiation of neurons by trans-synaptically binding to PTPRD (By similarity). {ECO:0000250|UniProtKB:P59823, ECO:0000250|UniProtKB:P59824, ECO:0000269|PubMed:127... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-35275
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
11/14/2023

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
  • intellectual disability, X-linked 21 Monarch
HI Evidence:
  • PUBMED: 26350204
    Grozeva et al (2015) performed targeted next gen sequencing for 565 genes in 986 individuals with moderate to severe intellectual disability. Three affected males were identified with predicted loss of function variants (c.148C>T/p.R50*); (c.889C>T/p.R297*); (c.606dupT/p.Ile203Tyrfs*8).
  • PUBMED: 21484992
    Franek et al (2011) reported a family consisting of two brothers with moderate intellectual disability, seizures, and dysmorphic features. Through targeted sequencing of nine known X-linked intellectual disability genes, both brothers were found to have a maternally inherited deletion of exons 1-5 of IL1RAPL1 (2-6 in the updated transcript NM_014271.4), which includes the first coding exon and is predicted to result in complete absence of protein product.
  • PUBMED: 21271657
    Behnecke et al (2011) reported a male individual with intellectual disability, global delays, dysmorphic features, scoliosis, and strabismus who had a de novo 300 kb intragenic deletion, which includes exon 2 of the gene, which is the first coding exon and includes the start methionine.
  • PUBMED: 25167861
    Redin et al (2014) reported a proband with moderate intellectual disability who was found to have a maternally inherited 10 bp deletion c.894_903 (p.Trp299Thrfs*18). A similarly affected brother was then found to have a de novo hemizygous deletion of the entire exon 7, which would be predicted to be out of frame. This deletion was found to have originated on the maternal allele, suggesting that the inherited 10 bp deletion that the mother carried may predispose to genomic instability leading to the larger deletion event. Both variants in this family would be predicted to result in loss of function.
  • PUBMED: 18801879
    Piton et al (2008) sequenced IL1RAPL1 in a cohort of 142 individuals with autism spectrum disorder and reported a de novo frameshifting variant in exon 9 (p.Ile367Serfs*9) in a female with a diagnosis of Asperger syndrome. Functional studies showed that this resulted in loss of function. In addition, authors reported a male proband with intellectual disability and autistic features, who had two brothers, one with pervasive developmental disorder - not otherwise specified, and the other with mild intellectual disability and repetitive behaviors. All three were found to have a deletion in IL1RAPL1, spanning exons 3-7. This is predicted to result a frameshift (p.Ala28Glufs*15), truncating the majority of the protein and leading to loss of function. This deletion was found to be inherited from the reportedly unaffected mother.
  • PUBMED: 22031302
    Mikhail et al. (2011) reported a male individual with global developmental delay, intellectual disability, and dysmorphic facial features who had a 1.07 Mb intragenic deletion detected via array CGH that contains exons 2-6 that was inherited from a reportedly unaffected mother. Exon 2 is the first coding exon of this gene; this deletion includes the start methionine and would be predicted to result in loss of function.
HI Evidence Comments:
Haploinsufficiency of IL1RAPL1 is associated with an X-linked neurological disorder characterized by intellectual disability and/or autism. Affected individuals are typically male and often have inherited the variant through their mother (PMID:21484992; PMID:25167861; PMID:18801879; PMID:22031302; PMID:21933724), though de novo variants have also been described (PMID:21484992; PMID:18801879). Women who are heterozygous for loss of function variants in IL1RAPL1 are variably affected. Of note, X-inactivation studies have been performed in carriers, with inconsistent results and the general perception that results are not predictive of whether a female carrier will be affected (PMID:22031302; PMID:21484992; PMID:21271657; PMID:27470653). Additional evidence of haploinsufficiency of IL1RAPL1 includes: PMID:21933724 (Youngs et al (2012), who reported a 15-year old male with autism, mild intellectual disability, hyperopia, behavior abnormalities, and dysmorphic features who had a 950 kb deletion that includes exons 3 through the 3' end of the gene. This was inherited from his mother, who had a history of learning difficulties, and was also found in his maternal half-brother who has intellectual disability and similar facial features. Other family members (both male and female) were reported to have similar facial features and intellectual disability but were not available for testing. Additionally, several reports of similar multi-exon, in-frame intragenic deletions have been reported in several large families with strong evidence of segregation through multiple generations of affected individuals. These deletions would be predicted to result in the loss of approximately 30% of the resulting protein (PMID:21484992; PMID: 21271657; PMID: 19012350). Also, gross deletions containing IL1RAPL1 in addition to several other genes have been reported as part of a contiguous gene deletion syndrome. Zhang et al (PMID:15300857) compared deletions involving IL1RPL1 to deletions of the same region that did not contain IL1RPL1, and showed that those deletions that contained IL1RAPL1 were associated with intellectual disability in the affected individuals. Finally, complex rearrangements involving IL1RAPL1 predicted to disrupt gene function have also been reported (PMID:14610352; PMID:26290131; PMID:27470653; PMID:18005360).
NOTE:

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)
NOTE:

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Genomic View

Select assembly: (NC_000023.10) (NC_000023.11)