%0 Journal Article %J Hum Mutat %D 2020 %T Phenotypic expansion in KIF1A-related dominant disorders: A description of novel variants and review of published cases. %A Montenegro-Garreaud, Ximena %A Hansen, Adam W %A Khayat, Michael M %A Chander, Varuna %A Grochowski, Christopher M %A Jiang, Yunyun %A Li, He %A Mitani, Tadahiro %A Kessler, Elena %A Jayaseelan, Joy %A Shen, Hua %A Gezdirici, Alper %A Pehlivan, Davut %A Meng, Qingchang %A Rosenfeld, Jill A %A Jhangiani, Shalini N %A Madan-Khetarpal, Suneeta %A Scott, Daryl A %A Abarca-Barriga, Hugo %A Trubnykova, Milana %A Gingras, Marie-Claude %A Muzny, Donna M %A Posey, Jennifer E %A Liu, Pengfei %A Lupski, James R %A Gibbs, Richard A %X

KIF1A is a molecular motor for membrane-bound cargo important to the development and survival of sensory neurons. KIF1A dysfunction has been associated with several Mendelian disorders with a spectrum of overlapping phenotypes, ranging from spastic paraplegia to intellectual disability. We present a novel pathogenic in-frame deletion in the KIF1A molecular motor domain inherited by two affected siblings from an unaffected mother with apparent germline mosaicism. We identified eight additional cases with heterozygous, pathogenic KIF1A variants ascertained from a local data lake. Our data provide evidence for the expansion of KIF1A-associated phenotypes to include hip subluxation and dystonia as well as phenotypes observed in only a single case: gelastic cataplexy, coxa valga, and double collecting system. We review the literature and suggest that KIF1A dysfunction is better understood as a single neuromuscular disorder with variable involvement of other organ systems than a set of discrete disorders converging at a single locus.

%B Hum Mutat %V 41 %P 2094-2104 %8 2020 12 %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/32935419?dopt=Abstract %R 10.1002/humu.24118 %0 Journal Article %J Genet Med %D 2019 %T Atlas-CNV: a validated approach to call single-exon CNVs in the eMERGESeq gene panel. %A Chiang, Theodore %A Liu, Xiuping %A Wu, Tsung-Jung %A Hu, Jianhong %A Sedlazeck, Fritz J %A White, Simon %A Schaid, Daniel %A Andrade, Mariza de %A Jarvik, Gail P %A Crosslin, David %A Stanaway, Ian %A Carrell, David S %A Connolly, John J %A Hakonarson, Hakon %A Groopman, Emily E %A Gharavi, Ali G %A Fedotov, Alexander %A Bi, Weimin %A Leduc, Magalie S %A Murdock, David R %A Jiang, Yunyun %A Meng, Linyan %A Eng, Christine M %A Wen, Shu %A Yang, Yaping %A Muzny, Donna M %A Boerwinkle, Eric %A Salerno, William %A Venner, Eric %A Gibbs, Richard A %X

PURPOSE: To provide a validated method to confidently identify exon-containing copy-number variants (CNVs), with a low false discovery rate (FDR), in targeted sequencing data from a clinical laboratory with particular focus on single-exon CNVs.

METHODS: DNA sequence coverage data are normalized within each sample and subsequently exonic CNVs are identified in a batch of samples, when the target log ratio of the sample to the batch median exceeds defined thresholds. The quality of exonic CNV calls is assessed by C-scores (Z-like scores) using thresholds derived from gold standard samples and simulation studies. We integrate an ExonQC threshold to lower FDR and compare performance with alternate software (VisCap).

RESULTS: Thirteen CNVs were used as a truth set to validate Atlas-CNV and compared with VisCap. We demonstrated FDR reduction in validation, simulation, and 10,926 eMERGESeq samples without sensitivity loss. Sixty-four multiexon and 29 single-exon CNVs with high C-scores were assessed by Multiplex Ligation-dependent Probe Amplification (MLPA).

CONCLUSION: Atlas-CNV is validated as a method to identify exonic CNVs in targeted sequencing data generated in the clinical laboratory. The ExonQC and C-score assignment can reduce FDR (identification of targets with high variance) and improve calling accuracy of single-exon CNVs respectively. We propose guidelines and criteria to identify high confidence single-exon CNVs.

%B Genet Med %V 21 %P 2135-2144 %8 2019 Sep %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/30890783?dopt=Abstract %R 10.1038/s41436-019-0475-4 %0 Journal Article %J Am J Med Genet A %D 2018 %T The phenotypic spectrum of Xia-Gibbs syndrome. %A Jiang, Yunyun %A Wangler, Michael F %A McGuire, Amy L %A Lupski, James R %A Posey, Jennifer E %A Khayat, Michael M %A Murdock, David R %A Sanchez-Pulido, Luis %A Ponting, Chris P %A Xia, Fan %A Hunter, Jill V %A Meng, Qingchang %A Murugan, Mullai %A Gibbs, Richard A %X

Xia-Gibbs syndrome (XGS: OMIM # 615829) results from de novo truncating mutations within the AT-Hook DNA Binding Motif Containing 1 gene (AHDC1). To further define the phenotypic and molecular spectrum of this disorder, we established an XGS Registry and recruited patients from a worldwide pool of approximately 60 probands. Additional de novo truncating mutations were observed among 25 individuals, extending both the known number of mutation sites and the range of positions within the coding region that were sensitive to alteration. Detailed phenotypic examination of 20 of these patients via clinical records review and data collection from additional surveys showed a wider age range than previously described. Data from developmental milestones showed evidence for delayed speech and that males were more severely affected. Neuroimaging from six available patients showed an associated thinning of the corpus callosum and posterior fossa cysts. An increased risk of both scoliosis and seizures relative to the population burden was also observed. Data from a modified autism screening tool revealed that XGS shares significant overlap with autism spectrum disorders. These details of the phenotypic heterogeneity of XGS implicate specific genotype/phenotype correlations and suggest potential clinical management guidelines.

%B Am J Med Genet A %V 176 %P 1315-1326 %8 2018 06 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/29696776?dopt=Abstract %R 10.1002/ajmg.a.38699