Initial Outcomes from the Undiagnosed Diseases Network Reveal Promising Number of Diagnoses

Members of the Undiagnosed Diseases Network (UDN) published a summary of the progress that was made by the network during the first twenty months of accepting applicants in the New England Journal of Medicine. During that time, the network accepted 601 participants that remained undiagnosed by traditional medical practices. Of those who completed their UDN evaluation in the first twenty months, 35% were given a diagnosis. Many of these diagnoses are rare genetic diseases including 31 previously unknown syndromes.

To learn more about this study, read the press releases associated with the publication from Stanford Medicine and Baylor College of Medicine.

New coverage associated with this publication:


Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease. Splinter K, Adams DR, Bacino CA, Bellen HJ, Bernstein JA, Cheatle-Jarvela AM, Eng CM, Esteves C, Gahl WA, Hamid R, Jacob HJ, Kikani B, Koeller DM, Kohane IS, Lee BH, Loscalzo J, Luo X, McCray AT, Metz TO, Mulvihill JJ, Nelson SF, Palmer CGS, Phillips JA 3rd, Pick L, Postlethwait JH, Reuter C, Shashi V, Sweetser DA, Tifft CJ, Walley NM, Wangler MF, Westerfield M, Wheeler MT, Wise AL, Worthey EA, Yamamoto S, Ashley EA, Undiagnosed Diseases Network. N Engl J Med. 2018 Oct 10.


Overactive Protein at the Cell Surface May Cause Neurological Symptoms

MRI scan photoResearchers from the NIH Undiagnosed Diseases Network (UDN) clinical site published a study of a novel mutation found in a 46-year-old woman suffering from progressive muscle weakness and muscle spasms. This mutation in the BAI2 gene was spontaneous and is not present in either of the woman’s parents. The BAI2 gene encodes a type of signaling protein called a G protein-coupled receptor, and is found primarily in nerve cells. A mutation that caused a change in BAI2’s function in nerves might result in symptoms of muscle weakness and spasms.

To understand whether the mutation in BAI2 could cause the patient’s symptoms, the researchers collaborated with UDN Gene Function researchers from Emory University funded by the National Institute of Neurological Disorders and Stroke (NINDS) to study the mutant BAI2 gene in cells grown in the laboratory. By carefully studying the molecular properties of BAI2, the researchers made two key observations. First, the mutant gene results in a functional protein that is present on the surface of cells in larger amounts than the normal protein. This is important because G protein-coupled receptors typically work by receiving signals at the surface of cells. Second, the mutant version of BAI2 has an enhanced ability to transmit signals to the cell, possibly due to its increased presence at the cell surface. These findings suggest this mutation in BAI2 results in an overactive signaling protein in the nerve cells of the patient.

While these results are promising, and suggest a possible genetic cause for this patient’s neurological condition, it is difficult to prove such a diagnosis. Ideally, additional patients will be found with similar mutations and symptoms to show definitively that the BAI2 gene mutation causes the observed symptoms. Further exploration of mutations in BAI2 in neurological conditions is particularly promising because many G protein-coupled receptors are “druggable” proteins, so drugs to inhibit BAI2 function could be developed in the future to treat these conditions.


A disease-associated mutation in the adhesion GPCR BAI2 (ADGRB2) increases receptor signaling activity. Purcell RH, Toro C, Gahl WA, Hall RA. Hum Mutat. 2017 Sep 10.


Precision Medicine Approach Reveals Targeted Therapy for Neurological Disorder

A new study from Undiagnosed Diseases Network (UDN) researchers shows how careful study of a genetic condition can be critical for determining the best possible treatment. In a recent manuscript, UDN investigators from Baylor College of Medicine studied 5 individuals with similar neurological conditions characterized by a developmental delay and difficulty with mobility and speech. All five individuals had a mutation in the same gene, CACNA1A. CACNA1A encodes the information to make part of a protein called a calcium channel that is important for the function of neurons. Four of the five individuals had that exact same change, but one was unique. The unique mutation was seen in a ten-year-old girl named Avery who was enrolled as a participant in the UDN.

It was known that other mutations in CACNA1A lead to a spectrum of neurological disorders, so the researchers tested whether the new mutations caused a loss of function of the calcium channel. Given that Avery had more severe symptoms than the other four patients, it was possible her unique mutation resulted in a less functional calcium channel than the channel from the other four patients. To test this idea, the UDN researchers modeled each patient mutation within a model organism, the fruit fly. These mutations caused similar neurological defects in the fly compared to the symptoms seen in the patients. Surprisingly, the calcium channel with change analogous to Avery’s mutation was not less functional, it was more functional than the normal protein, allowing more calcium to enter nerve cells. This excess calcium can be toxic to nerve cells, which would lead to the defects. This finding had important implications for Avery’s treatment. Patients with CACNA1A mutations are often given medication to help compensate for the lack of function in the calcium channel, however Avery is now being treated with a drug to block the overactive calcium channel based on this research. This study highlights the power of a precision medicine based approach in which targeted therapies are designed for individuals based on precise molecular diagnoses. 

To learn more about Avery and this diagnosis, check out this story on or visit Avery's Participant Page on the UDN Coordinating Center website.


Clinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially. Luo X, Rosenfeld JA, Yamamoto S, Harel T, Zuo Z, Hall M, Wierenga KJ, Pastore MT, Bartholomew D, Delgado MR, Rotenberg J, Lewis RA, Emrick L, Bacino CA, Eldomery MK, Coban Akdemir Z, Xia F, Yang Y, Lalani SR, Lotze T, Lupski JR, Lee B, Bellen HJ, Wangler MF, Members of the UDN. PLoS Genet. 2017 Jul 24. 13(7): e1006905.


The Cause of a Rare Neurological Disorder Uncovered by the UDN

Brain ImageResearchers from the UDN have used DNA sequencing efforts combined with laboratory experimental efforts to determine the cause of a previously unknown neurological disorder characterized by delayed development, intellectual disability, abnormal facial development and reduced response to pain. UDN investigators used DNA sequencing to determine that three children with similar neurological and intellectual deficiencies had mutations at the same location in a single copy of a gene named EBF3, which was previously not associated with any known disease. While it is unlikely that three patients with similar symptoms would have the same gene mutated as a coincidence, UDN researchers sought to prove that this mutation was the cause of this rare disease. Using human cells in culture in the laboratory, they were able to show that the mutations in each of these patients disrupted the function of EBF3 as a regulator of gene expression. In addition, they took advantage of the fact that disrupting the fruit fly version of the EBF3 gene results in a neurological defect in the flies. The UDN researchers were able to show that this condition in flies could be reversed by adding back a normal copy of the human EBF3 gene, but not the mutant copy from these three patients. Taken together, this evidence strongly suggests that it is the mutation in EBF3 causing this neurological disorder. This study highlights the power of the UDN approach of pairing clinical and laboratory scientists in order to solve complex medical mysteries.


A Syndromic Neurodevelopmental Disorder Caused by De Novo Variants in EBF3.  Chao HT, Davids M, Burke E, Pappas JG, Rosenfeld JA, McCarty AJ, Davis T, Wolfe L, Toro C, Tifft C, Xia F, Stong N, Johnson TK, Warr CG; Undiagnosed Diseases Network, Yamamoto S, Adams DR, Markello TC, Gahl WA, Bellen HJ, Wangler MF, Malicdan MC. Am J Hum Genet. 2016 Dec 21.

A Single Mutation Acts as a Molecular Switch for Sex Determination

female and male sex symbols

In humans, sex determination is normally regulated by the inheritance of specific chromosomes, with females inheriting two X chromosomes and males inheriting and an X and a Y chromosome.  The Y chromosome directs formation of the male reproductive system and without a Y chromosome an individual will develop with a female reproductive system.  However, genetic defects can occasionally lead to sexual organ development that does not correspond to the chromosomal makeup of an individual.

A research team including members of the Undiagnosed Diseases Network have identified the cause of a subset of these genetic disorders.  By sequencing DNA from four different families they were able to show that remarkably a single specific mutation in a single gene (NR5A1) can act as a molecular switch, causing XX individuals to develop as a male and XY individuals to develop as a female.  This study highlights the power of sharing genetic data both inside and outside of the UDN in aiding the generation of a diagnosis for rare disorders.


A recurrent p.Arg92Trp variant in steroidogenic factor-1 (NR5A1) can act as a molecular switch in human sex development.  Bashamboo A, Donohoue PA, Vilain E, Rojo S, Calvel P, Seneviratne SN, Buonocore F, Barseghyan H, Bingham N, Rosenfeld JA, Mulukulta SN, Jain M, Burrage L, Dhar S, Balasubramanyam A, Lee B, Members of UDN, Eozenou C, Suntharalingham JP, de Silva K, Lin L, Bignon-Topalovic J, Poulat F, Lagos CF, McElreavey K, Achermann JC. Hum Mol Genet. 2016 Jul 4. pii: ddw186.

This page last reviewed on May 8, 2019