%0 Journal Article %J HGG Adv %D 2021 %T Germline mutation in : a heterogeneous, multi-systemic developmental disorder characterized by transcriptional dysregulation. %A Hansen, Adam W %A Arora, Payal %A Khayat, Michael M %A Smith, Leah J %A Lewis, Andrea M %A Rossetti, Linda Z %A Jayaseelan, Joy %A Cristian, Ingrid %A Haynes, Devon %A DiTroia, Stephanie %A Meeks, Naomi %A Delgado, Mauricio R %A Rosenfeld, Jill A %A Pais, Lynn %A White, Susan M %A Meng, Qingchang %A Pehlivan, Davut %A Liu, Pengfei %A Gingras, Marie-Claude %A Wangler, Michael F %A Muzny, Donna M %A Lupski, James R %A Kaplan, Craig D %A Gibbs, Richard A %X

germline variation in was recently reported to associate with a neurodevelopmental disorder. We report twelve individuals harboring putatively pathogenic or inherited variants in , detail their phenotypes, and map all known variants to the domain structure of and crystal structure of RNA polymerase II. Affected individuals were ascertained from a local data lake, pediatric genetics clinic, and an online community of families of affected individuals. These include six affected by missense variants (including one previously reported individual), four clinical laboratory samples affected by missense variation with unknown inheritance-with yeast functional assays further supporting altered function-one affected by a in-frame deletion, and one affected by a C-terminal frameshift variant inherited from a largely asymptomatic mother. Recurrently observed phenotypes include ataxia, joint hypermobility, short stature, skin abnormalities, congenital cardiac abnormalities, immune system abnormalities, hip dysplasia, and short Achilles tendons. We report a significantly higher occurrence of epilepsy (8/12, 66.7%) than previously reported (3/15, 20%) (p value = 0.014196; chi-square test) and a lower occurrence of hypotonia (8/12, 66.7%) than previously reported (14/15, 93.3%) (p value = 0.076309). -related developmental disorders likely represent a spectrum of related, multi-systemic developmental disorders, driven by distinct mechanisms, converging at a single locus.

%B HGG Adv %V 2 %8 2021 Jan 14 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33665635?dopt=Abstract %R 10.1016/j.xhgg.2020.100014 %0 Journal Article %J Hum Mutat %D 2021 %T Phenotypic and protein localization heterogeneity associated with AHDC1 pathogenic protein-truncating alleles in Xia-Gibbs syndrome. %A Khayat, Michael M %A Li, He %A Chander, Varuna %A Hu, Jianhong %A Hansen, Adam W %A Li, Shoudong %A Traynelis, Josh %A Shen, Hua %A Weissenberger, George %A Stossi, Fabio %A Johnson, Hannah L %A Lupski, James R %A Posey, Jennifer E %A Sabo, Aniko %A Meng, Qingchang %A Murdock, David R %A Wangler, Michael %A Gibbs, Richard A %X

Xia-Gibbs syndrome (XGS) is a rare Mendelian disease typically caused by de novo stop-gain or frameshift mutations in the AT-hook DNA binding motif containing 1 (AHDC1) gene. Patients usually present in early infancy with hypotonia and developmental delay and later exhibit intellectual disability (ID). The overall presentation is variable, however, and the emerging clinical picture is still evolving. A detailed phenotypic analysis of 34 XGS individuals revealed five core phenotypes (delayed motor milestones, speech delay, low muscle tone, ID, and hypotonia) in more than 80% of individuals and an additional 12 features that occurred more variably. Seizures and scoliosis were more frequently associated with truncations that arise before the midpoint of the protein although the occurrence of most features could not be predicted by the mutation position. Transient expression of wild type and different patient truncated AHDC1 protein forms in human cell lines revealed abnormal patterns of nuclear localization including a diffuse distribution of a short truncated form and nucleolar aggregation in mid-protein truncated forms. Overall, both the occurrence of variable phenotypes and the different distribution of the expressed protein reflect the heterogeneity of this syndrome.

%B Hum Mutat %V 42 %P 577-591 %8 2021 May %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/33644933?dopt=Abstract %R 10.1002/humu.24190 %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