GPR161-related medulloblastoma predisposition: research report

Evidence base and its limits. This report rests on web-search abstract snippets and secondary summaries. The PMC full text was blocked by a reCAPTCHA page, so I did not read the primary paper's full text. I did not extract variant-level details (cDNA/protein changes, de novo versus inherited, ClinVar IDs) or the functional-assay results. I found no post-2021 case reports or cohorts. Per your attribution rules, items marked [gap] have no source in hand. Items marked [inference] are my reasoning beyond the sources. Every PMID or identifier I could not confirm is marked unverified.

Source classes - Primary literature: Begemann et al., J Clin Oncol 2020, PMID:31609649 (PubMed, PMC6943973). - Commentary: Cancer Discovery 9(12):1645. I saw only its title. - Reviews: PMC7658916 and PMC11341988, as quoted in search snippets. - Gene-panel curation: Genomics England PanelApp panel 259. - Model-organism papers: Mukhopadhyay 2013, Shimada 2018, and an eLife knock-in study, seen through search summaries only.

1. Disease information

• Entity. GPR161-related medulloblastoma predisposition is a germline, heterozygous tumor-predisposition syndrome. It is defined by infant-onset SHH-subgroup medulloblastoma.
• Identifiers. MONDO:1010204 comes from your template and I did not verify it. OMIM, Orphanet, ICD, and MeSH were not checked [gap]. Medulloblastoma itself is OMIM #155255, and my search surfaced that entry.
• Synonyms. "Germline GPR161 mutations predispose to pediatric medulloblastoma" is the paper's title phrase. Other names [gap].
• Data source. The data come from patient cohorts in one study: families plus 1,044 medulloblastoma cases from international cohorts. They are not EHR-derived.
• Lump/split, germline versus somatic (design decisions §3a). Keep this germline syndrome separate from the somatic SHH-medulloblastoma entry. The reported tumor spectrum is a single tumor type.
• Authors' own caveat. The authors wrote that "Additional studies are needed to identify a potential broader tumor spectrum associated with germline GPR161 mutations." Whether this is a syndrome or a single-tumor susceptibility is open.

2. Etiology

• Cause. Heterozygous germline GPR161 loss-of-function variants, followed by a somatic loss of the wild-type allele.
• Begemann 2020 (PMID:31609649, human clinical): "We identified heterozygous germline mutations in the G protein-coupled receptor 161 (GPR161) gene in six patients with infant-onset medulloblastoma (median age, 1.5 years)."
• The same abstract: "Molecular tumor profiling revealed a loss of heterozygosity at GPR161 in all affected MB_SHH_ tumors… no additional somatic driver events."
• Genetic risk modifiers. None known [gap].
• Environmental risk and protective factors. None identified [gap]. Gene-environment interactions [gap].
• Protective factors. None identified [gap].

3. Phenotypes

All figures come from the single index study (six patients), which I read only in abstract form.

• Quality of life. [gap]
• Penetrance and exact frequencies. [gap]. Do not infer them from a six-patient ascertainment series.
• HPO term IDs. These are from memory, so verify each by lookup before binding.

4. Genetic and molecular information

• Gene. GPR161, G protein-coupled receptor 161, on chromosome 1q24.
• In this repo the HGNC CURIE is lowercase hgnc:. I did not look up the number, so no hgnc: ID is given here.
• The chromosome position is from memory.
• Variants. Per the abstract, heterozygous, in six patients. The variant list is not read [gap]. Pull it from the paper's tables and from ClinVar.
• ClinGen validity. [gap]. Check for a CGGV record with just clingen-list.
• PanelApp lists GPR161 as Green (high evidence) for "Childhood solid tumours cancer susceptibility" (panel 259).
• A gene-panel rating is not a ClinGen assertion, so do not record it as classified_by: CLINGEN.
• Allele frequency. Search snippets quote the paper: "the carrier frequency is approximately 1 in 42,000 to 1 in 125,000 individuals". The gnomAD source for this was not checked.
• Second hit. Begemann 2020: "Analysis of 226 MB_SHH_ tumors revealed somatic copy-neutral loss of heterozygosity of chromosome 1q as the hallmark characteristic of GPR161 deficiency and the primary mechanism for biallelic inactivation."
• This is classic two-hit biology.
• Copy-neutral LOH on 1q fits the locus.
• Functional consequence. Loss of function is the working model [inference from LOH plus gene biology]. The paper's functional assays [gap].
• Epigenetic, chromosomal, and modifier-gene information. [gap]

5. Environmental information

None reported [gap]. No infectious agents are relevant.

6. Mechanism

Causal chain (the demonstrated links are the human genetic steps; most of the mechanism is from mouse work, and I only saw summaries of those papers): 1. A germline heterozygous GPR161 loss-of-function allele is present in all cells. Demonstrated in patients (PMID:31609649). 2. This leads to a somatic loss of the wild-type allele in a cerebellar lineage, mainly by copy-neutral LOH of 1q. Demonstrated in the patients' tumors, which all showed LOH at GPR161. 3. Biallelic loss of GPR161 removes a ciliary G-protein-coupled receptor that normally constitutively activates cAMP and PKA. Mouse data (Mukhopadhyay 2013): "Gpr161 constitutively activates cAMP formation…" 4. Loss of PKA activity reduces Gli3 repressor formation. Mouse: "Gpr161 knockout embryos lack Gli3 repressor." 5. This results in unrestrained, Smoothened-independent Hedgehog pathway activity. Inferred for human tumors. It matches the SHH-subgroup restriction and the absence of other somatic drivers. 6. Expansion and hyperproliferation of cerebellar granule neuron progenitors follows. Mouse (Shimada 2018): conditional deletion in neural stem cells or granule cell progenitors "increased downstream activity of the Shh pathway by restricting Gli3-mediated repression, causing more extensive generation and proliferation of GC progenitors." 7. Tumors arise, and tumor incidence and severity are higher with earlier deletion. Mouse (Shimada 2018). Early embryonic onset fits the infant presentation in humans [inference].

Suggested ontology terms (look up each before binding): - Cell types: cerebellar granule cell precursor (CL), neural stem cell. - GO processes: smoothened signaling pathway, adenylate cyclase-activating G protein-coupled receptor signaling, cilium-dependent signaling. - Anatomy: cerebellum (UBERON). - Cellular component: primary cilium.

Not covered. Immune, metabolic, omics, single-cell, and CRISPR-screen data [gap].

7. Anatomical structures affected

• Organ and cell level. Cerebellum, with granule neuron progenitors as the likely cell of origin [inference from mouse data, plus the usual SHH-medulloblastoma biology].
• Cell of origin is derived from the pathograph in dismech. Mark the somatic second-hit node variant_origin: SOMATIC and bind the cell type there.
• Lateralization. [gap]

8. Temporal development

• Onset. Infancy, median 1.5 years (PMID:31609649).
• Progression, staging, and remission. [gap]
• Critical period. Infancy is the period of tumor presentation. The mechanism of the age restriction is [gap].

9. Inheritance and population

• Inheritance. Autosomal dominant predisposition with a somatic second hit. Penetrance [gap].
• Because penetrance is unknown, 5% of infant SHH cases carrying these variants does not give a penetrance figure.
• Frequency among cases. The paper reports about 5% of infant SHH medulloblastoma in its cohorts. A 2024 review reports 3.4% of pediatric SHH medulloblastoma (PMC11341988, snippet only).
• These figures use different denominators: infant SHH versus pediatric SHH.
• Carrier frequency. About 1 in 42,000 to 1 in 125,000, as quoted from the paper above.
• Incidence and prevalence of the syndrome. [gap]
• De novo versus inherited, parental carriers, family history, founder effects, and sex ratio. [gap]. The paper began from families, so a familial component is implied, but I did not read the pedigree details.

10. Diagnostics

• Germline testing. A review recommends it: "patients with MB_SHH should be tested for germline ELP1 mutations, especially those presenting outside of infancy, and for germline GPR161 mutations, particularly those presenting in infancy" (PMC7658916).
• Tumor LOH or 1q copy-neutral LOH is a flag for GPR161 deficiency (PMID:31609649).
• Tumor diagnostics. The standard medulloblastoma workup applies.
• The molecular subgroup is SHH. Methylation profiling is the usual classifier [inference, not source-checked].
• Differential. SUFU, PTCH1, and TP53 germline predisposition, and ELP1 for older SHH patients.
• Surveillance protocols. [gap]. I found no GPR161-specific surveillance guideline. Do not borrow SUFU or PTCH1 protocols without saying so.

11. Outcome and prognosis

[gap]. No GPR161-specific survival or functional-outcome data were found. The same applies to prognostic factors and the quality-of-life measures.

12. Treatment

• No GPR161-specific treatment is documented [gap].
• Dismech curation note. Do not transfer SHH-inhibitor (SMO) logic to this entry as a treatment claim.
• The mouse mechanism implies the defect lies downstream of Smoothened [inference]. If so, SMO inhibitors would be unlikely to work. That is a hypothesis, not a finding.
• Standard infant medulloblastoma therapy and clinical trials [gap].

13. Prevention

• Prevention and counseling. Genetic counseling and cascade testing are standard for AD predisposition, but I have no GPR161-specific guidance [gap].
• Radiation caution. There is no GPR161 evidence on radiation sensitivity [gap]. Do not extrapolate from other syndromes.

14. Other species

• Naturally occurring disease. [gap]. Check OMIA.
• Ortholog. A mouse ortholog exists (Gpr161). NCBI Gene IDs were not looked up.

15. Model organisms

• Germline knockout mouse (Mukhopadhyay 2013, summary only).
• Embryonic lethal by E10.5, with "ventralization throughout the rostro-caudal extent of the neural tube", craniofacial abnormalities, and open fore/mid brain regions and caudal neural tube defects.
• Evidence class: model organism.
• Conditional deletion (Shimada 2018, Cell Reports, seen as scite report 29386106).
• Deletion in neural stem cells or granule cell progenitors increased granule cell progenitor production.
• "Earlier deletion of Gpr161 during embryogenesis increased tumor incidence and severity." Evidence class: model organism.
• Fidelity to human disease: mouse tumors versus human infant SHH-medulloblastoma [gap]. The cilium-dependence finding is mouse-specific.
• Ciliary-localization knock-in (eLife, via search summary). A ciliary-localization-defective but cAMP-competent allele showed progenitor expansion in the intermediate neural tube that depends on Gli3 repressor loss. This suggests ciliary localization matters.
• Human-model mismatch.
• The heterozygous carrier phenotype in mice is not described in my sources.
• Whether the human neural tube defect signal is real is open.
• Consider a HUMAN_MODEL_MISMATCH discussion on these.

Curation leads, not yet checked

1. Read the full text of PMID:31609649 and copy the variant list.
2. Verify the PMIDs of Shimada 2018 and Mukhopadhyay 2013. Neither PMID is verified.
3. Run just clingen-list and check ClinVar for GPR161.
4. Fetch the cohort and survivor reviews and confirm the 3.4% figure.
5. Search for GPR161 papers after 2021, which my searches did not surface.
6. Confirm MONDO:1010204.

Sources: - Begemann et al., PubMed 31609649 - PMC6943973 - Cancer Discovery 9(12):1645 - PMC7658916 - PMC11341988 - PanelApp panel 259 - Shimada 2018 (scite) - Mukhopadhyay lab summary - eLife knock-in study

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

• PMC:PMC7658916: "patients with MB_SHH should be tested for germline ELP1 mutations, especially those presenting outside of infancy, and for germline GPR161 mutations, particularly those presenting in infancy"
• closest text in source: "Furthermore, we suggest that patients with MBSHH should be tested for germline ELP1 mutations, especially those presenting outside of infancy, and for germline GPR161 mutations, particularly those presenting in infancy"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Every term resolved, and every label the report gave matched.