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A Variant in TAF1 Is Associated with a New Syndrome with Severe Intellectual Disability and Characteristic Dysmorphic Features

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A Variant in TAF1 Is Associated with a New Syndrome with Severe Intellectual Disability and Characteristic Dysmorphic Features bioRxiv preprint doi: https://doi.org/10.1101/014050; this version posted January 21, 2015. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under Research Article aCC-BY 4.0 International license. Vol. X, No. X / January 2015 / Article 1 A variant in TAF1 is associated with a new syndrome with severe intellectual disability and characteristic dysmorphic features JASON A. O’RAWE1,2,#,YIYANG WU1,2,#,ALAN ROPE3,LAURA T. JIMENEZ BARRÓN1,4, JEFFREY SWENSEN5,HAN FANG1,DAVID MITTELMAN6,7,GARETH HIGHNAM6,REID ROBISON7,8,EDWARD YANG9,KAI WANG7,8,10, AND GHOLSON J. LYON1,2,8 1Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, NY, USA 2Stony Brook University, Stony Brook, NY, USA 3Department of Medical Genetics, Northwest Kaiser Permanente, Portland, OR, USA 4Centro de Ciencias Genomicas, Universidad Nacional Autonoma de Mexico, Cuernavaca, Morelos, MX 5Caris Life Sciences, Phoenix, Arizona, USA 6Gene by Gene, Ltd., Houston, TX, USA 7Tute Genomics, Ltd., Provo, UT, USA 8Utah Foundation for Biomedical Research, Salt Lake City, UT, USA 9Department of Radiology, Boston Children’s Hospital, Boston, MA, USA 10Zilkha Neurogenetic Institute, Department of Psychiatry and Preventive Medicine, University of Southern California, Los Angeles, CA, USA #Co-first authors *Corresponding author: [email protected] Compiled January 20, 2015 We describe the discovery of a new genetic syndrome, RykDax syndrome, driven by a whole genome sequencing (WGS) study of one family from Utah with two affected male brothers, presenting with severe intellectual disability (ID), a characteristic intergluteal crease, and very distinctive facial features including a broad, upturned nose, sagging cheeks, downward sloping palpebral fissures, prominent periorbital ridges, deep-set eyes, relative hypertelorism, thin up- per lip, a high-arched palate, prominent ears with thickened helices, and a pointed chin. This Caucasian family was recruited from Utah, USA. Illumina-based WGS was performed on 10 members of this family, with additional Complete Genomics-based WGS performed on the nu- clear portion of the family (mother, father and the two affected males). Using WGS datasets from 10 members of this family, we can increase the reliability of the biological inferences with an integrative bioinformatic pipeline. In combination with insights from clinical evaluations and medical diagnostic analyses, these DNA sequencing data were used in the study of three plausible genetic disease models that might uncover genetic contribution to the syndrome. We found a 2 to 5-fold difference in the number of variants detected as being relevant for various disease models when using different sets of sequencing data and analysis pipelines. We de- rived greater accuracy when more pipelines were used in conjunction with data encompassing a larger portion of the family, with the number of putative de-novo mutations being reduced by 80%, due to false negative calls in the parents. The boys carry a maternally inherited mis- sense variant in a X-chromosomal gene TAF1, which we consider as disease relevant. TAF1 is the largest subunit of the general transcription factor IID (TFIID) multi-protein complex, and our results implicate mutations in TAF1 as playing a critical role in the development of this new intellectual disability syndrome. 1. INTRODUCTION [4–6] in a variety of research and clinical settings [7]. Com- putational tools for processing and analyzing these sequence Dramatic cost reductions and rapid advancements in the devel- data have been developed in parallel, and many are now freely opment of efficient sequencing technologies [1–3] have led to available and straightforward to implement [4]. In this context, widespread use of exome and whole genome sequencing (WGS) biomedical exome sequencing and WGS has led to the discov- bioRxiv preprint doi: https://doi.org/10.1101/014050; this version posted January 21, 2015. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under Research Article aCC-BY 4.0 International license. Vol. X, No. X / January 2015 / Article 2 ery of the genetic basis for many conditions, including Miller collected from the elder sibling, and neurotransmitter metabo- Syndrome [8] and others [9]. lites, tetrahydrobiopterin (BH4) and neopterin (N) profile were The intellectual impetus for this study included how to iden- screened. tify the major genetic contribution to a particular syndrome in only one proband or two affected siblings, in the absence of A.3. Custom X CGH array and X-chromosome skewing assay other affected people with the same known syndrome. This task 500 ng of each research participant’s DNA was labeled with 5’- is much easier in the presence of multiple affected people spread Cy3 tagged nanomers (NimbleGen) while a female control was out over two or more generations [10, 11], but this is usually not labeled with Cy5 nonamers. After purification by isopropanol the case for most biomedical presentations of idiopathic disor- precipitation, 31 ug each of labeled research participant and ders. Genetic discovery can also be easier in consanguineous reference DNA were combined. The mixture was hybridized pedigrees with autosomal recessive conditions [12, 13], but such to a custom NimbleGen 720K Chromosome X Specific Array consanguinity is not widespread in many parts of the world [14]. for 42 hours at 42C in a MAUI Hybridization System (BioMicro We instead focused on an analysis that initially included one Systems). The array was then washed according to the manufac- family with only two siblings that are both afflicted by an idio- turer’s recommendation (Nimblegen) and immediately scanned. pathic syndrome, and so we utilized WGS to cover as much of After scanning, fluorescence intensity raw data was extracted the genome as we could, particularly as any number of mutated from the scanned images of the array using NimbleScan v2.6 nucleotides in the genome might influence some phenotype software. For each of the spots on the array, normalized log2 during embryogenesis or postnatal life [15–33]. ratios of the Cy3-labeled research participant sample vs the Cy5- This Caucasian family was recruited from Utah, USA. reference sample were generated using the SegMNT program. Illumina-based WGS was performed on 10 members of this fam- The data was visualized with Nexus 6.1 software (Biodiscovery). ily, with additional Complete Genomics-based WGS performed X-chromosome skewing assay analyses were performed us- on the nuclear portion of the family (mother, father and the ing an adaptation of the technique described by Allen et al. two affected males). Sequence data were processed with a num- (1992) [34]. ber of bioinformatics pipelines. Using comprehensive datasets generated by an aggregation of results stemming from these B. Whole Genome Sequencing and analysis methods pipelines, we can increase the reliability of the biological infer- Two different sequencing strategies were employed. Initial se- ences stemming from these data. In combination with insights quencing efforts focused on whole genome sequencing using from clinical evaluations and medical diagnostic analyses, these the Complete Genomics (CG) sequencing and analysis pipeline DNA sequencing data were used in the study of three plausible v2.0 for the mother, father and two affected boys. Additional genetic disease models that might uncover genetic contribution whole genome sequencing was performed subsequent to this to the syndrome. initial effort, using the Illumina HiSeq 2000 sequencing platform. The mother, father, two affected boys and six other immediate 2. MATERIALS AND METHODS family members were sequenced using the Illumina HiSeq 2000. This study consists of two methodological components, clini- Raw sequencing data stemming from Illumina sequencing was cal and genomic sequencing/analysis. The clinical component processed by a variety of analysis pipelines and subsequently includes research participant enrollment, clinical evaluation, di- pooled with variants detected by the CG sequencing an analy- agnostic analyses and a detailed clinical report. The genomic sis pipeline. Downstream and functional annotation tools were sequencing component includes whole genome sequencing as used to evaluate variants detected by the various methods. well as downstream analyses aimed at annotating and assigning B.1. Complete Genomics whole genome sequencing and variant de- biological function to detected genomic variants. tection After quality control to ensure lack of genomic degradation, we A. Clinical methods sent 10ug DNA samples to Complete Genomics (CG) at Moun- A.1. Enrollment of research participants tain View, California for sequencing. The whole-genome DNA The collection and the analysis of DNA was conducted by the was sequenced with a nanoarray-based short-read sequencing- Utah Foundation for Biomedical Research, as approved by the by-ligation technology, including an adaptation of the pairwise Institutional Review Board (IRB) (Plantation, Florida). Written end-sequencing strategy. Reads were mapped to the Genome informed consent was also obtained from all study participants, Reference Consortium assembly GRCh37. Due to the propri- and research was carried out in compliance with the Helsinki etary data formats,
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