%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 %0 Journal Article %J BMC Med Genet %D 2013 %T Exome sequencing of a patient with suspected mitochondrial disease reveals a likely multigenic etiology. %A Craigen, William J %A Graham, Brett H %A Wong, Lee-Jun %A Scaglia, Fernando %A Lewis, Richard Alan %A Bonnen, Penelope E %K Adult %K Computational Biology %K DNA Helicases %K Exome %K Genetic Diseases, X-Linked %K Genetic Loci %K Homozygote %K Humans %K Male %K Mitochondrial Diseases %K Multifunctional Enzymes %K Mutation, Missense %K Nephrolithiasis %K Oculocerebrorenal Syndrome %K Pedigree %K Phenotype %K Phosphoric Monoester Hydrolases %K RNA Helicases %K RNA, Ribosomal, 16S %K Sequence Analysis, DNA %K Spinocerebellar Ataxias %K Spinocerebellar Degenerations %X

BACKGROUND: The clinical features of mitochondrial disease are complex and highly variable, leading to challenges in establishing a specific diagnosis. Despite being one of the most commonly occurring inherited genetic diseases with an incidence of 1/5000, ~90% of these complex patients remain without a DNA-based diagnosis. We report our efforts to identify the pathogenetic cause for a patient with typical features of mitochondrial disease including infantile cataracts, CPEO, ptosis, progressive distal muscle weakness, and ataxia who carried a diagnosis of mitochondrial disease for over a decade.

METHODS: Whole exome sequencing and bioinformatic analysis of these data were conducted on the proband.

RESULTS: Exome sequencing studies showed a homozygous splice site mutation in SETX, which is known to cause Spinocerebellar Ataxia, Autosomal Recessive 1 (SCAR1). Additionally a missense mutation was identified in a highly conserved position of the OCRL gene, which causes Lowe Syndrome and Dent Disease 2.

CONCLUSIONS: This patient's complex phenotype reflects a complex genetic etiology in which no single gene explained the complete clinical presentation. These genetic studies reveal that this patient does not have mitochondrial disease but rather a genocopy caused by more than one mutant locus. This study demonstrates the benefit of exome sequencing in providing molecular diagnosis to individuals with complex clinical presentations.

%B BMC Med Genet %V 14 %P 83 %8 2013 Aug 16 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/23947751?dopt=Abstract %R 10.1186/1471-2350-14-83