FAM177A1 Related Disorder

Charlotte and Cooper are siblings followed by a team at the UDN-Stanford who discovered their disease causing variant on FAM177A1 via whole genome sequencing in 2019. You can find detailed health history information here.

Through gene-matching databases, we know of a handful of other cases with similar clinical presentations and LOF variants on FAM177A1. We know that there are more patients out there and we will likely find them soon now that this variant has been identified and with papers about FAM177A1 scheduled to be published in the next few months.

Patients are typically born full term and healthy but then fall behind developmentally. Symptoms include macrocephaly, global development delays, behavior abnormality, abnormal brain MRI, abnormal muscle tone, gait disturbance, seizures, arthritis and recurrent infections.

Patients typically experience a range of neurodevelopmental manifestations from an early age compounded by subsequent neurodegenerative changes that may include progressive motor decline, progressive and intractable seizures, arthritis and/or neuro-inflammatory indications. Patients require full support for all aspects of daily living and require coordination of clinical expertise across multiple domains including but not limited to genetics, neurology, rheumatology, neuroimmunology, and ophthalmology. There are currently no disease-specific treatment options.

Diagnosis requires gene sequencing and deletion/duplication analysis. All patients are considered to have loss of function (LOF) of the FAM177A1 gene caused by deletions, non-sense or frameshift variants. Known patients live in the Middle East, Europe, and United States with the majority of families from Middle Eastern and Latinx heritage. The condition is likely significantly underdiagnosed because the gene is currently not included in many genetic panels or analyses, some of the variants are small deletions that are challenging to detect, and genetic analysis suggests a founder variant in Latinx patients, which are underrepresented in biomedical research.

Information about this previously understudied gene is accumulating at a relatively rapid pace.

Symptoms

FAM177A1 Related Disorder
Symptoms Include

Intellectual disability/global developmental delay
Autism
Macrocephaly/Large head size
Seizures
Sleep disturbance
Ataxia
Unusual gate or walking pattern
Congenital cataracts
Muscle tone issues (low/high tone, contractures)
Arthritis
Upslanted palpebral fissures
Frequent infections

Videos of FAM177A1 Patients

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What We Know About FAM177A1

In patients with mutations on FAM177A1, both copies of the gene are inactivated either by deletions, frameshift, or nonsense mutations; autosomal recessive compound heterozygous or homozygous.
The phenotype includes macrocephaly, global developmental delay, diffuse hypotonia, autism, seizures, progressive motor decline, arthritis, and congenital cataracts.
FAM177A1 is an evolutionarily conserved and ubiquitously expressed gene that encodes a protein of unknown function.
Fam177a1 localizes to the Golgi complex and endoplasmic reticulum.
Fam177a1 is required for normal Golgi function.
FAM177A1 fibroblasts are currently at Mayo Clinic for metabolomics analysis.
Knockout FAM177A1 zebrafish are currently being studied at the MOSC at Washington U and at the Metabolomics Core at Mayo Clinic.
FAM177A1 is also being studied by Dr. Pietro De Camillo’s lab at Yale in conjunction with their work on lipid transport and VPS13B.
Jackson Labs are currently developing FAM177A1 mouse model. The FAM177A1 knock-out mice are viable and will be phenotypes in late 2023.

FAM177A1 Genetic Information

Charlotte and Cooper had exome sequencing done as part of a research study at the University of Washington and have also been followed by the Rare Genomics Institute. There was initial hope that variants on the following genes might have caused their disease but there has been no further evidence to support this: LAMA5, NSD1and EZH2 genes.

In the spring of 2016, Charlotte and Cooper were accepted into the National Institute of Health’s Undiagnosed Diseases Network (NIH-UDN) program at Stanford University where extensive medical review and work-up was completed including whole genome sequencing.

Finally, in 2019 after four years and multiple rounds of whole genome sequencing, the UDN found deletions on both copies of both kids’ FAM177A1 gene.

The GRCh37 coordinates of the deletion are:

Chr14:35513595 – 35521629 (8kb) – encompasses exon 1
Chr14:35546986 – 355566772 (9.7kb) – encompasses exon 4-5

The GRCh38 coordinates of the deletion are:

Chr14: 35044389 – 35052423 (8kb) – encompasses exon 1
Chr14: 35077780 – 35087566 (9.7kb) – encompasses exons 4-5

The gene covers around 38,500 bases. Other information:Exons: 7, Coding exons: 5, Transcript length: 3,254 bps, Translation length: 213 residues (this is the length of the protein). Ensembl link

The FAM177A1 deletions were detected via short read genome sequencing run on illumina platform. The deletions were called in the short read genome data through a research bioinformatics pipeline developed at HudsonAlpha (who performed the sequencing). The deletions were subsequently confirmed orthogonally at a clinical CLIA lab which used a qPCR deletion/duplication assay. Long read sequencing was not required to detect these deletions, though it should be able to. It's also expected that typical deletion/duplication analyses with single exon resolution should be able to detect the deletions as well.

Very little was known about FAM177A1, but 4 siblings with overlapping symptoms to Charlotte and Cooper’s, and variants on this gene, were found in a research paper (Accelerating Novel Candidate Gene Discovery in Neurogenetic Disorders via Whole-Exome Sequencing of Prescreened Multiplex Consanguineous Families

Alazami 2015). Today, through gene-matching databases, we know of about 15 of other cases from 8 families with similar clinical presentations and loss of function (LOF) variants on FAM177A1.

In Feb 2022, we finally connected with another FAM family. You can read about that in our blog. We have since connected with another family in the US with two affected kids and know of about 15 more in the Middle East and Europe. We know that there are more patients out there and hope to find them soon!

Zebrafish with the function of FAM177A1 knocked out are currently being studied at the MOSC at Washington University and at the Metabolomics Core at Mayo Clinic, and the FAM177A1 protein is being studied at the De Camilli Lab at Yale.

Genetic Information

Poster presented about FAM177A1 at the 2020 ACMG Conference

FAM177A1 Poster from ACMG Conference copy.jpg

Genome

Summary of FAM177A1 Research Literature

FAM177A1 Inhibits IL-1β–Induced Signaling by Impairing TRAF6–Ubc13 Association

Liao 2021

IL-1β is a pro-inflammatory cytokine involved in a wide spectrum of immune and inflammatory pathways. One of the main activating signals in the IL-1β pathway is TRAF6 mediated polyubiquination resulting in subsequent activation of key transcription factors, NF-KB and AP-1, for induction of downstream inflammatory genes. The signaling pathway is negatively regulated by deubiquitinating enzymes such as A20, USP4, and USP19 which disrupt TRAF-6 signaling and prevent expression of inflammatory mediators. To identify additional regulators of the IL-1β signaling pathway, the authors used luciferase reporting assays to screen a library of more than 16,000 cDNA expression plasmids. In this screen, FAM177A1 was identified as a negative regulator of the IL-1β signaling cascade. The mechanism of this regulation was explored using various expression constructs of FAM177A1 in HEK293T cell lines. The authors found that overexpression of FAM177A1 led to decreased activation of IL-1β -induced inflammatory gene transcription in a dose-dependent manner, while knockdown enhanced the pathway. FAM177A1 specifically regulated IL-1β signaling by competitively binding to TRAF6 and inhibiting interaction with Ubc13. As a result, TRAF-6-mediated polyubiquination and downstream induction of inflammatory gene transcription is prevented by FAM177A1. This is one of the only publications to date that has defined and characterized a function of FAM177A1 in the immune system.

Accelerating Novel Candidate Gene Discovery in Neurogenetic Disorders via Whole-Exome Sequencing of Prescreened Multiplex Consanguineous Families

Alazami 2015

The aim of this study was to discover disease-causing genes in neurologic disorders, primarily those with poor clinical recognizability. The authors analyzed WES data from 143 multiplex families with consanguineous parents and probands who presented with intellectual disability. In a multi-step WES approach, the regions of homozygosity were prioritized for elucidation of disease genes. If no disease gene was apparent, the WES data for each individual was analyzed with the assumption of identifying a novel disease gene. Sequencing of this cohort revealed 69 novel recessively-inherited genes which had not previously been associated with disease. One disease gene, FAM177A1, was identified in a family with 4 affected children who presented with macrocephaly, intellectual disability, dolichocephaly, and mild obesity. They share a frameshift mutation (c.297_298insA:p.L99fs) which is predicted to cause loss of protein function. This publication reported the first cases implicating FAM177A1 as a disease causing gene, yet, with limited clinical details on the family.

Noninvasive imaging of microRNA124a-mediated repression of the chromosome 14 ORF 24 gene during neurogenesis

Ko 2009

Micro-RNAs are 22-basepair single-stranded molecules that carry out many diverse roles in the human body by binding to mRNA targets. A class of miRNAs are found in neurons to regulate neuronal development. One miRNA, miR124a, is expressed highly in actively differentiating neural progenitors and mature neurons. In this study, the function of miR124a was studied using qRT-PCR assays of key stem cell genes during neuronal differentiation of P19 cells. In order to identify novel targets of miR124a, microarray data revealing seed sequences was analyzed in tandem with data from an miRNA database to predict targets of miR124a. One of the potential targets, FAM177A1/c14orf24, was investigated with in vitro luciferase assays to monitor the expression. The studies revealed that miRNA124a mediated the repression of FAM177A1/c14orf24 during peak neurogenesis, however, FAM177A1/c14orf24 was not expressed prior to or after neuronal differentiation. FAM177A1/c14orf24 was found to be highly expressed in the cytoplasm of proliferating P19 cells.

Co-stimulatory CD28 and transcription factor NFKB1 gene variants affect idiopathic recurrent miscarriages

Misra 2016

Women who experience recurrent pregnancy loss have been shown to have aberrant immune system responses to pregnancy including a decreased total amount of regulatory T cells (Treg). The development of Treg cells involves CD28 co-stimulatory activation of downstream pathways. As a result of CD28 signaling, NF-KB family of transcription factors are activated to initiate Treg cell development. Polymorphisms in the CD28 and NF-KB genes have previously been linked to autoimmune disorders and may have a role in recurrent pregnancy loss. To study this hypothesis, the authors compared functional variants in CD28 and NF-KB in 200 women with recurrent pregnancy loss to 300 fertile control women. The results showed three genotypes in both genes associated with risk for miscarriage. In women with these genotypes, the abundance of transcripts of CD28 and FAM177A1 was decreased as compared to control women. These findings suggest a role for FAM177A1 in immune regulation and may be implicated in autoimmune diseases.

Identification of a Novel Candidate Locus for Juvenile Idiopathic Arthritis at 14q13.2 in the Latvian Population by Association Analysis with Microsatellite Markers

Sjakste 2010

Juvenile idiopathic arthritis (JIA) is a clinically heterogenous disorder associated with genetic and environmental risk factors. A region of the genome, 14q, contains a cluster of proteasomal genes in which allelic variations in these genes have been studied for their effect on the production of immunoglobulin E as a key part of JIA pathophysiology. Within this region, several other non-proteasomal genes exist but the association with JIA has never been investigated. The authors explored additional genes in this region including FAM177A1, KIAA0391, and PSMA6, by genotyping a population of individuals with JIA compared to those without. Direct sequencing showed two variable components of the HMS602 marker of the FAM177A1 gene which was associated with risk for JIA.

A large-scale plasma proteome Mendelian randomization study identifies novel causal plasma proteins related to primary binary cholangitis.

Hongqun Yang 2023

Primary biliary cholangitis (PBC) is a progressive chronic autoimmune cholestatic liver disease characterized by the destruction of small intrahepatic bile ducts leading to biliary cirrhosis. Liver biopsy is required in the diagnosis of Antimitochondrial antibody-negative patients. Therefore, novel biomarkers are needed for the non-invasive diagnosis of PBC. To identify novel biomarkers for PBC, we conducted large-scale plasma proteome Mendelian randomization (MR). The findings suggest that higher FAM1771 expression protects against PBC in this serum proteomics study.

Literature