I am the mom of the first two children recently diagnosed with an ultra-rare genetic disease. For the last 16 years, my husband Doug and I have been lost in a turbulent sea, struggling to navigate our diagnostic quest. But, just recently, we have gained momentum and feel we are now finding our way. Seventeen years ago, we had our first child, Nash. He was healthy and reached his developmental milestones on schedule. Seventeen months later, we excitedly welcomed our daughter Charlotte. Although healthy and seemingly typical at birth, she soon fell behind developmentally: her muscle tone was floppy, she smiled late, and was hard to engage. We began consulting with clinicians about Charlotte’s delays. We tried physical therapy, occupational therapy, and speech therapy; we met with neurologists, developmental specialists, and geneticists. Nothing seemed to work, and no one had an explanation for why our precious girl was delayed and falling further and further behind. Eventually, it became clear that this was not just a “delay” — Charlotte would likely require a lifetime of intense support and medical intervention. We were scared and sad but plowed ahead, providing all we could for our sweet girl. When Charlotte was 4, we considered having a third child. At this point, Charlotte had extensive genetic testing and all known disorders had been ruled out. She was thought to have a “de-novo” genetic variant, and we were told that we were no more likely to have another child with disabilities than any other family. So, we rolled the dice and, about a year later, gave birth to a darling little boy named Cooper. Cooper was healthy at birth, but soon we felt a dreadful sense of déjà vu as he fell behind developmentally. Although there was no way to know for sure, because Charlotte remained undiagnosed, we and our medical team felt that Cooper had whatever it was that challenged Charlotte. This clearly wasn’t a de-novo variant; this was most likely an ultra-rare recessive genetic disorder. Although we love our kids fiercely, this was shocking. More appointments and more therapies, all made exponentially harder without a diagnosis and a lack of hope for any precise treatment. We worried about how we would meet their needs and find solutions for their struggles. Add in the frustration, fear, and loneliness of them being undiagnosed, and we found ourselves in rough seas, on a ragged ship that was taking on more and more water. Over the years, we’ve been fortunate to have excellent care for our kids; however, despite exome sequencing and a devoted Seattle-based medical team, Charlotte and Cooper remained undiagnosed. Then, I heard about the Undiagnosed Diseases Network (UDN). One of the silver linings of having two kids likely affected by the same unknown genetic variant is that your family is quite interesting to clinicians and researchers — it’s probably one of the primary reasons we were accepted into the UDN in 2015, when Cooper was 5 and Charlotte was 10. We were thrilled that someone was willing to take a deep dive into our case. Yet, even as it appeared that our case might be “solvable,” it proved instead to be quite challenging to our expanded team. Finally, in 2019 after four years and multiple rounds of whole-genome sequencing, the UDN found large deletions on both copies of both kids’ FAM177A1 gene. Very little was known about this gene, but four siblings with overlapping symptoms to Charlotte and Cooper’s, and variants on this gene, were found in a research paper: we knew we were onto something! In the hopes of finding more patients and generating interest in our gene, we made a short film about our journey which can be viewed on our website, www.FAM177A1.com. Today, through gene-matching databases, we know of a handful of other cases with similar clinical presentations and loss of function (LOF) variants on FAM177A1. We have yet to personally connect with other “Fam” families, but this is something we desperately want to happen. We know that there are more patients out there and hope to find them soon, now that this variant has been identified and because papers about FAM177A1 are scheduled to be published in the next few months. 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 by Dr. Pietro De Camilli’s lab at Yale. What we know about Charlotte and Copper’s disease-causing variant, FAM177A1, so far is this: • In patients with mutations on FAM177A1, both copies of the gene are inactivated, either by large deletions or by nonsense mutations, in our case autosomal recessive compound heterozygous. • Phenotype includes macrocephaly, global developmental delay, diffuse hypotonia, autism, seizures, progressive motor decline, cataracts. • The FAM177A1 gene makes the FAM177A1 protein, which is a small protein that is expressed throughout development and throughout embryonic tissues. • FAM177A1 is localized in the Golgi complex and endoplasmic reticulum. • Studies with Brefeldin A have demonstrated that FAM177A1 is required for normal Golgi function. • FAM177A1 binds to the VPS13B protein, which has been implicated in the transport of lipids between intracellular membranes; it’s hypothesized that FAM177A1 may also be involved in this process. After a 16-year diagnostic quest, we finally have a diagnosis, and information about this previously understudied gene is accumulating at a relatively rapid pace. Our team of clinicians and researchers think that a treatment is within reach. We are determined and are urgently seeking more information as Charlotte’s motor function is now in decline and Cooper’s seizures are worsening. We have just recently started the FAM177A1 Research Fund and are raising money to fund research and develop therapies to increase the quality of life of Charlotte and Cooper and others like them. We are fully committed to making an impact on this ultra-rare and neglected disorder. After 16 years of idling without a diagnosis, we are quickly gaining momentum. We have a devoted and talented Scientific Advisory Board (SAB) guiding us on our road to treatment. We still don’t know why Charlotte and Cooper, our sweet, rare zebras, are struggling so much. We have no road map, no treatment. But, we are learning more every day and a treatment or cure is possible! This is an incredibly exciting time for genetics and precision medicine. We can do this! We will never give up. I have a dream that someday, soon, my family will cruise on a sturdy ship, with a good map and strong sails that have been precisely made for FAM177A1.