%0 Journal Article %J Hum Mutat %D 2020 %T A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders. %A Ngo, Kathie J %A Rexach, Jessica E %A Lee, Hane %A Petty, Lauren E %A Perlman, Susan %A Valera, Juliana M %A Deignan, Joshua L %A Mao, Yuanming %A Aker, Mamdouh %A Posey, Jennifer E %A Jhangiani, Shalini N %A Coban-Akdemir, Zeynep H %A Eric Boerwinkle %A Donna M Muzny %A Nelson, Alexandra B %A Hassin-Baer, Sharon %A Poke, Gemma %A Neas, Katherine %A Geschwind, Michael D %A Grody, Wayne W %A Richard A Gibbs %A Geschwind, Daniel H %A James R Lupski %A Below, Jennifer E %A Nelson, Stanley F %A Fogel, Brent L %K Cerebellar Ataxia %K DNA Copy Number Variations %K Exome %K Exome Sequencing %K Genetic Association Studies %K Genetic Linkage %K Genetic Predisposition to Disease %K Humans %K Microsatellite Repeats %K Nervous System Diseases %X

Genetic ataxias are associated with mutations in hundreds of genes with high phenotypic overlap complicating the clinical diagnosis. Whole-exome sequencing (WES) has increased the overall diagnostic rate considerably. However, the upper limit of this method remains ill-defined, hindering efforts to address the remaining diagnostic gap. To further assess the role of rare coding variation in ataxic disorders, we reanalyzed our previously published exome cohort of 76 predominantly adult and sporadic-onset patients, expanded the total number of cases to 260, and introduced analyses for copy number variation and repeat expansion in a representative subset. For new cases (n = 184), our resulting clinically relevant detection rate remained stable at 47% with 24% classified as pathogenic. Reanalysis of the previously sequenced 76 patients modestly improved the pathogenic rate by 7%. For the combined cohort (n = 260), the total observed clinical detection rate was 52% with 25% classified as pathogenic. Published studies of similar neurological phenotypes report comparable rates. This consistency across multiple cohorts suggests that, despite continued technical and analytical advancements, an approximately 50% diagnostic rate marks a relative ceiling for current WES-based methods and a more comprehensive genome-wide assessment is needed to identify the missing causative genetic etiologies for cerebellar ataxia and related neurodegenerative diseases.

%B Hum Mutat %V 41 %P 487-501 %8 2020 Feb %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/31692161?dopt=Abstract %R 10.1002/humu.23946 %0 Journal Article %J Neuron %D 2017 %T Loss of Nardilysin, a Mitochondrial Co-chaperone for α-Ketoglutarate Dehydrogenase, Promotes mTORC1 Activation and Neurodegeneration. %A Yoon, Wan Hee %A Sandoval, Hector %A Nagarkar-Jaiswal, Sonal %A Jaiswal, Manish %A Yamamoto, Shinya %A Haelterman, Nele A %A Putluri, Nagireddy %A Putluri, Vasanta %A Sreekumar, Arun %A Tos, Tulay %A Aksoy, Ayse %A Donti, Taraka %A Graham, Brett H %A Ohno, Mikiko %A Nishi, Eiichiro %A Hunter, Jill %A Muzny, Donna M %A Carmichael, Jason %A Shen, Joseph %A Arboleda, Valerie A %A Nelson, Stanley F %A Wangler, Michael F %A Karaca, Ender %A Lupski, James R %A Bellen, Hugo J %K Animals %K Autophagy %K Drosophila %K Drosophila melanogaster %K Drosophila Proteins %K Ketoglutarate Dehydrogenase Complex %K Ketoglutaric Acids %K Lysine %K Mechanistic Target of Rapamycin Complex 1 %K Metalloendopeptidases %K Mitochondria %K Molecular Chaperones %K Multiprotein Complexes %K Neurodegenerative Diseases %K TOR Serine-Threonine Kinases %X

We previously identified mutations in Nardilysin (dNrd1) in a forward genetic screen designed to isolate genes whose loss causes neurodegeneration in Drosophila photoreceptor neurons. Here we show that NRD1 is localized to mitochondria, where it recruits mitochondrial chaperones and assists in the folding of α-ketoglutarate dehydrogenase (OGDH), a rate-limiting enzyme in the Krebs cycle. Loss of Nrd1 or Ogdh leads to an increase in α-ketoglutarate, a substrate for OGDH, which in turn leads to mTORC1 activation and a subsequent reduction in autophagy. Inhibition of mTOR activity by rapamycin or partially restoring autophagy delays neurodegeneration in dNrd1 mutant flies. In summary, this study reveals a novel role for NRD1 as a mitochondrial co-chaperone for OGDH and provides a mechanistic link between mitochondrial metabolic dysfunction, mTORC1 signaling, and impaired autophagy in neurodegeneration.

%B Neuron %V 93 %P 115-131 %8 2017 Jan 04 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/28017472?dopt=Abstract %R 10.1016/j.neuron.2016.11.038 %0 Journal Article %J Am J Hum Genet %D 2017 %T A Recurrent De Novo Variant in NACC1 Causes a Syndrome Characterized by Infantile Epilepsy, Cataracts, and Profound Developmental Delay. %A Schoch, Kelly %A Meng, Linyan %A Szelinger, Szabolcs %A Bearden, David R %A Stray-Pedersen, Asbjorg %A Busk, Oyvind L %A Stong, Nicholas %A Liston, Eriskay %A Cohn, Ronald D %A Scaglia, Fernando %A Rosenfeld, Jill A %A Tarpinian, Jennifer %A Skraban, Cara M %A Deardorff, Matthew A %A Friedman, Jeremy N %A Akdemir, Zeynep Coban %A Walley, Nicole %A Mikati, Mohamad A %A Kranz, Peter G %A Jasien, Joan %A McConkie-Rosell, Allyn %A McDonald, Marie %A Wechsler, Stephanie Burns %A Freemark, Michael %A Kansagra, Sujay %A Freedman, Sharon %A Bali, Deeksha %A Millan, Francisca %A Bale, Sherri %A Nelson, Stanley F %A Lee, Hane %A Dorrani, Naghmeh %A Goldstein, David B %A Xiao, Rui %A Yang, Yaping %A Posey, Jennifer E %A Martinez-Agosto, Julian A %A Lupski, James R %A Wangler, Michael F %A Shashi, Vandana %K Alleles %K Amino Acid Sequence %K Brain %K Cataract %K Child %K Child, Preschool %K Female %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Infant %K Intellectual Disability %K Magnetic Resonance Imaging %K Male %K Microcephaly %K Mutation, Missense %K Neoplasm Proteins %K Pedigree %K Phenotype %K Repressor Proteins %K Spasms, Infantile %X

Whole-exome sequencing (WES) has increasingly enabled new pathogenic gene variant identification for undiagnosed neurodevelopmental disorders and provided insights into both gene function and disease biology. Here, we describe seven children with a neurodevelopmental disorder characterized by microcephaly, profound developmental delays and/or intellectual disability, cataracts, severe epilepsy including infantile spasms, irritability, failure to thrive, and stereotypic hand movements. Brain imaging in these individuals reveals delay in myelination and cerebral atrophy. We observe an identical recurrent de novo heterozygous c.892C>T (p.Arg298Trp) variant in the nucleus accumbens associated 1 (NACC1) gene in seven affected individuals. One of the seven individuals is mosaic for this variant. NACC1 encodes a transcriptional repressor implicated in gene expression and has not previously been associated with germline disorders. The probability of finding the same missense NACC1 variant by chance in 7 out of 17,228 individuals who underwent WES for diagnoses of neurodevelopmental phenotypes is extremely small and achieves genome-wide significance (p = 1.25 × 10). Selective constraint against missense variants in NACC1 makes this excess of an identical missense variant in all seven individuals more remarkable. Our findings are consistent with a germline recurrent mutational hotspot associated with an allele-specific neurodevelopmental phenotype in NACC1.

%B Am J Hum Genet %V 100 %P 343-351 %8 2017 Feb 02 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/28132692?dopt=Abstract %R 10.1016/j.ajhg.2016.12.013