Fetal anomalies
Gene: LOXL3 Amber List (moderate evidence)I don't know
Biallelic variants reported in association with Stickler syndrome in 2 unrelated families. Also identified in one individual with non-syndromic Pierre Robin sequence who had a CNV also.
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PMID 34787502 Sood et al 2021 - proband with non-syndromic Pierre Robin sequence - homozygous missense LOXL3 variant identified. Sibling also had non-syndromic PRS, but genetic testing declined by family. In addition 551 kb chr10q26.2 duplication identified, no parental testing information provided, not previously reported to be associated with CL/P.
PMID 30362103 Chan et al 2019 - report father and son with Stickler syndrome and homozygous LOXL3 missense variants. Predominantly ocular phenotype with no antenatal features reported.
PMID: 29802726 Khan et al 2018 - genotyping of 258 probands with non-syndromic cleft palate (nsCP) and their parents, focusing in particular on common missense variant p.Ile615Phe. Identified four Phe/Phe homozygotes, report significant association between infant’s homozygote Phe/Phe genotype and the risk of nsCP, compared to common Ile/Ile homozygotes
PMID 26957899 Li et al 2016 - A homozygous frameshift mutation (c.39dup; p.L14Afs*21) and a compound heterozygous frameshift mutation (c.39dup; p.L14Afs*21 and c.594delG; p.Q199Kfs*35) in LOXL3 were separately identified in two of 298 probands with early-onset high myopia.
PMID: 26307084 Zhang et al 2015 - Mice lacking LOXL3 exhibited perinatal lethality and were noted to have cleft palate and spinal deformity.
PMID: 25663169 Alzahrani et al 2015 - homozygous variant identified in 2 children with Stickler syndrome from the same family, both children had cleft lip/palate.
Sources: LiteratureCreated: 22 Feb 2022, 11:42 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Stickler syndrome; cleft lip/palate
Publications
Gene: loxl3 has been classified as Amber List (Moderate Evidence).
Gene: loxl3 has been classified as Amber List (Moderate Evidence).
gene: LOXL3 was added gene: LOXL3 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: LOXL3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LOXL3 were set to 25663169; 26307084; 26957899; 29802726; 30362103; 34787502 Phenotypes for gene: LOXL3 were set to Stickler syndrome; cleft lip/palate Review for gene: LOXL3 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.