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 December 1, 2017