Fetal anomalies
Gene: LRP6 Amber List (moderate evidence)I don't know
LoF variants known to be associated with tooth agenesis. In addition, x2 unrelated families from 2 different studies with heterozygous LRP6 variant had tooth agenesis and cleft lip/palate (PMID 29500247; 26963285). Growth failure reported in some individuals but unclear if prenatal in onset (PMID 26963285). Minor finger/ear anomalies reported in x2 patients (PMID 26387593; 30950205)- unlikely to be detected antenatally and one of the reported patients (30950205) had x2 chromosome deletions, one of which involved LRP6 and multiple other genes.
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PMID: 34306029 Huang et al 2021 - Heterozygous LRP6: c.2570G > A (p.R857H), harbored by six members of a Chinese family, including 4 with tooth agenesis. Sparse hair another phenotypic feature.
PMID: 33164649 Yu et al 2021 - identified 4 novel LRP6 heterozygous mutations in 4 of 77 oligodontia patients. One patient with a nonsense paternally inherited variant had a hypohidrotic ectodermal dysplasia phenotype - no antenatal features, father had oligodontia. Supportive functional evidence
PMID: 29500247 Basha et al 2018 - Nonsense LRP6 variant identified in a family with cleft lip/palate. Proband had bilateral cleft lip and palate with missing upper lateral incisors, mother had bilateral cleft lip. x1 unaffected brother but family members not reassessed for oligodontia after variant identified.
PMID: 28813618 Dinckan et al 2018 - heterozygous splice site LRP6 variant identified in 1 family with isolated tooth agenesis. Affected family members also had mild periocular hyperpigmentation and hypoplastic alae nasi - thought to be unrelated to phenotype
PMID: 26963285 Ockeloen et al 2016 - frameshift variant identified in patient with tooth agenesis and orofacial clefting - boy born with bilateral cleft lip, L) sided cleft of the alveolus and complete cleft of the hard and soft palate. Also noted to have growth retardation, hypermetropia and small median alveolar manibular cleft. Maternal relatives with variant had severe tooth agenesis but no clefting. Canonical splice site variant identified in a patient with isolated severe tooth agenesis. Targeted resequencing showed statistically significant enrichment of unique LRP6 variants in tooth agenesis patients (7/67 versus 13/706 controls), not orofacial clefting cohort. 4/7 of these patients required growth hormone therapy and 3/7 had clinodactyly in addition to dental anomalies.
PMID: 26387593 – Massink et al 2015 - x4 LoF heterozygous LRP6 variants identified in 4 unrelated families with isolated severe tooth agenesis. All affected members of one family showed minor anatomical variation of the ear and underdevelopment of the thumb
PMID: 30950205 Ross et al 2019 - Proband with oligodontia and thrombocytopenia, also had mild finger and ear anomalies. Array revealed an interstitial loss of 150 kb in 8p23.1 encompassing MCPH1 and ANGPT2 and an interstitial loss of 290 kb in 12p13.2 encompassing ETV6, BCL2L14 and LRP6.
Sources: LiteratureCreated: 7 Feb 2022, 4:01 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Tooth agenesis, selective, 7 - MIM#616724; cleft lip/palate
Publications
Gene: lrp6 has been classified as Amber List (Moderate Evidence).
Gene: lrp6 has been classified as Amber List (Moderate Evidence).
gene: LRP6 was added gene: LRP6 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: LRP6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: LRP6 were set to 16126904; 30950205; 26387593; 26963285; 28813618; 29500247; 33164649; 34306029 Phenotypes for gene: LRP6 were set to Tooth agenesis, selective, 7 - MIM#616724; cleft lip/palate Review for gene: LRP6 was set to AMBER
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at panelapp@genomicsengland.co.uk
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.