Fetal anomalies
Gene: FAT1 Green List (high evidence)Green List (high evidence)
No OMIM gene-disease association, but multiple affected individuals from unrelated families reported with biallelic FAT1 variants and syndromic features consisting of ocular anomalies, hand/foot malformations and nephropathy. Although diagnosis antenatally not yet reported, some phenotypic features are detectable antenatally.
PMID: 30862798 Larouchi et al 2019 - homozygous frameshift FAT1 variants identified in 10 affected individuals from 5 unrelated consanguineous families. The patients presented with syndromic features including ocular anomalies (ptosis, microphthalmia, coloboma, amblyopia), nephropathy (FSGS, proteinuria, haematuria), toe syndactyly and facial dysmorphism. Animal models showing that deletion of Fat1 leads to coloboma in mouse and zebrafish.
PMID 26905694 Gee et al 2016 – report recessive mutations in FAT1 in four unrelated consanguineous families with a combination of steroid-resistant nephrotic syndrome, tubular ectasia, haematuria and variable neurodevelopmental findings such ID, polymicrogyria and hydrocephalus. X1 child with pulmonary stenosis.
PMID: 34202629 Peluso et al 2021 – Homozygous FAT1 frameshift variant NM_005245.4:c.9729del identified in a child of consanguineous parents with bilateral anophthalmia and hand/foot malformations including - right split foot with 4 toes, 5 metacarpals, second toe duplication and preaxial polydactyly on the right hand. Patient also had congenital heart defects including VSD, ASD and bicuspid aortic valve. Proband also had a microarray which detected a maternally inherited 350 kb 15q26.3 duplication including OMIM morbid gene CERS3 (AR condition) and part of the OMIM morbid gene ADAMTS17 (AR condition). Mother healthy, CNV unrelated to patient’s phenotype.
PMID: 34013115 Fabretti et al 2021 – report 4 patients with biallelic FAT1 variants from 3 unrelated families with syndactyly, ophthalmologic and renal phenotype consistent with previously reported cases.
PMID: 33418956 Haug et al 2021 - Genetic analysis showed that proband with phenotypic features consistent with other reported cases was compound heterozygous for a frameshift FAT1 variant and 1.8Mb 4q35.2 del including FAT1.
PMID: 32902815 Rossanti et al 2021 – Biallelic FAT1 variants reported in a child with isolated mild proteinuria and no syndromic features
Sources: LiteratureCreated: 24 Jan 2022, 5:31 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
multiple congenital anomalies; nephropathy; ocular anomalies; hand and foot anomalies
Publications
Gene: fat1 has been classified as Green List (High Evidence).
Gene: fat1 has been classified as Green List (High Evidence).
gene: FAT1 was added gene: FAT1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: FAT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FAT1 were set to 30862798; 26905694; 34202629; 34013115; 33418956; 32902815 Phenotypes for gene: FAT1 were set to multiple congenital anomalies; nephropathy; ocular anomalies; hand and foot anomalies Review for gene: FAT1 was set to GREEN
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.