%0 Journal Article %J Hum Mutat %D 2022 %T A recurrent single-exon deletion in TBCK might be under-recognized in patients with infantile hypotonia and psychomotor delay. %A Dai, Hongzheng %A Zhu, Wenmiao %A Bo Yuan %A Walley, Nicole %A Schoch, Kelly %A Jiang, Yong-Hui %A Phillips, John A %A Jones, Melissa S %A Liu, Pengfei %A David R Murdock %A Burrage, Lindsay C %A Lee, Brendan %A Rosenfeld, Jill A %A Xiao, Rui %K DNA Copy Number Variations %K Exome %K Exome Sequencing %K Exons %K Humans %K Infant %K Muscle Hypotonia %K Muscular Diseases %K Protein Serine-Threonine Kinases %K Retrospective Studies %X

Advanced bioinformatics algorithms allow detection of multiple-exon copy-number variations (CNVs) from exome sequencing (ES) data, while detection of single-exon CNVs remains challenging. A retrospective review of Baylor Genetics' clinical ES patient cohort identified four individuals with homozygous single-exon deletions of TBCK (exon 23, NM_001163435.2), a gene associated with an autosomal recessive neurodevelopmental phenotype. To evaluate the prevalence of this deletion and its contribution to disease, we retrospectively analyzed single nucleotide polymorphism (SNP) array data for 8194 individuals undergoing ES, followed by PCR confirmation and RT-PCR on individuals carrying homozygous or heterozygous exon 23 TBCK deletions. A fifth individual was diagnosed with the TBCK-related disorder due to a heterozygous exon 23 deletion in trans with a c.1860+1G>A (NM_001163435.2) pathogenic variant, and three additional heterozygous carriers were identified. Affected individuals and carriers were from diverse ethnicities including European Caucasian, South Asian, Middle Eastern, Hispanic American and African American, with only one family reporting consanguinity. RT-PCR revealed two out-of-frame transcripts related to the exon 23 deletion. Our results highlight the importance of identifying single-exon deletions in clinical ES, especially for genes carrying recurrent deletions. For patients with early-onset hypotonia and psychomotor delay, this single-exon TBCK deletion might be under-recognized due to technical limitations of ES.

%B Hum Mutat %V 43 %P 1816-1823 %8 2022 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/36317458?dopt=Abstract %R 10.1002/humu.24497 %0 Journal Article %J Genet Med %D 2022 %T Retrospective analysis of a clinical exome sequencing cohort reveals the mutational spectrum and identifies candidate disease-associated loci for BAFopathies. %A Chen, Chun-An %A Lattier, John %A Zhu, Wenmiao %A Rosenfeld, Jill %A Wang, Lei %A Scott, Tiana M %A Du, Haowei %A Patel, Vipulkumar %A Dang, Anh %A Magoulas, Pilar %A Streff, Haley %A Sebastian, Jessica %A Svihovec, Shayna %A Curry, Kathryn %A Delgado, Mauricio R %A Hanchard, Neil A %A Lalani, Seema %A Marom, Ronit %A Madan-Khetarpal, Suneeta %A Saenz, Margarita %A Dai, Hongzheng %A Meng, Linyan %A Xia, Fan %A Bi, Weimin %A Liu, Pengfei %A Posey, Jennifer E %A Scott, Daryl A %A James R Lupski %A Eng, Christine M %A Xiao, Rui %A Bo Yuan %K Abnormalities, Multiple %K Actins %K Chromosomal Proteins, Non-Histone %K DNA-Binding Proteins %K Exome %K Hand Deformities, Congenital %K Humans %K Micrognathism %K Retrospective Studies %X

PURPOSE: BRG1/BRM-associated factor (BAF) complex is a chromatin remodeling complex that plays a critical role in gene regulation. Defects in the genes encoding BAF subunits lead to BAFopathies, a group of neurodevelopmental disorders with extensive locus and phenotypic heterogeneity.

METHODS: We retrospectively analyzed data from 16,243 patients referred for clinical exome sequencing (ES) with a focus on the BAF complex. We applied a genotype-first approach, combining predicted genic constraints to propose candidate BAFopathy genes.

RESULTS: We identified 127 patients carrying pathogenic variants, likely pathogenic variants, or de novo variants of unknown clinical significance in 11 known BAFopathy genes. Those include 34 patients molecularly diagnosed using ES reanalysis with new gene-disease evidence (n = 21) or variant reclassifications in known BAFopathy genes (n = 13). We also identified de novo or predicted loss-of-function variants in 4 candidate BAFopathy genes, including ACTL6A, BICRA (implicated in Coffin-Siris syndrome during this study), PBRM1, and SMARCC1.

CONCLUSION: We report the mutational spectrum of BAFopathies in an ES cohort. A genotype-driven and pathway-based reanalysis of ES data identified new evidence for candidate genes involved in BAFopathies. Further mechanistic and phenotypic characterization of additional patients are warranted to confirm their roles in human disease and to delineate their associated phenotypic spectrums.

%B Genet Med %V 24 %P 364-373 %8 2022 Feb %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/34906496?dopt=Abstract %R 10.1016/j.gim.2021.09.017 %0 Journal Article %J Genet Med %D 2020 %T CNVs cause autosomal recessive genetic diseases with or without involvement of SNV/indels. %A Bo Yuan %A Wang, Lei %A Liu, Pengfei %A Shaw, Chad %A Dai, Hongzheng %A Cooper, Lance %A Zhu, Wenmiao %A Anderson, Stephanie A %A Meng, Linyan %A Wang, Xia %A Wang, Yue %A Xia, Fan %A Xiao, Rui %A Braxton, Alicia %A Peacock, Sandra %A Schmitt, Eric %A Ward, Patricia A %A Vetrini, Francesco %A He, Weimin %A Chiang, Theodore %A Donna M Muzny %A Richard A Gibbs %A Beaudet, Arthur L %A Breman, Amy M %A Smith, Janice %A Cheung, Sau Wai %A Bacino, Carlos A %A Eng, Christine M %A Yang, Yaping %A James R Lupski %A Bi, Weimin %K Child %K DNA Copy Number Variations %K Exome Sequencing %K Exons %K Humans %K INDEL Mutation %K Retrospective Studies %X

PURPOSE: Improved resolution of molecular diagnostic technologies enabled detection of smaller sized exonic level copy-number variants (CNVs). The contribution of CNVs to autosomal recessive (AR) conditions may be better recognized using a large clinical cohort.

METHODS: We retrospectively investigated the CNVs' contribution to AR conditions in cases subjected to chromosomal microarray analysis (CMA, N = ~70,000) and/or clinical exome sequencing (ES, N = ~12,000) at Baylor Genetics; most had pediatric onset neurodevelopmental disorders.

RESULTS: CNVs contributed to biallelic variations in 87 cases, including 81 singletons and three affected sibling pairs. Seventy cases had CNVs affecting both alleles, and 17 had a CNV and a single-nucleotide variant (SNV)/indel in trans. In total, 94.3% of AR-CNVs affected one gene; among these 41.4% were single-exon and 35.0% were multiexon partial-gene events. Sixty-nine percent of homozygous AR-CNVs were embedded in homozygous genomic intervals. Five cases had large deletions unmasking an SNV/indel on the intact allele for a recessive condition, resulting in multiple molecular diagnoses.

CONCLUSIONS: AR-CNVs are often smaller in size, transmitted through generations, and underrecognized due to limitations in clinical CNV detection methods. Our findings from a large clinical cohort emphasized integrated CNV and SNV/indel analyses for precise clinical and molecular diagnosis especially in the context of genomic disorders.

%B Genet Med %V 22 %P 1633-1641 %8 2020 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/32576985?dopt=Abstract %R 10.1038/s41436-020-0864-8 %0 Journal Article %J Genet Med %D 2019 %T Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies. %A Bo Yuan %A Neira, Juanita %A Pehlivan, Davut %A Santiago-Sim, Teresa %A Song, Xiaofei %A Rosenfeld, Jill %A Posey, Jennifer E %A Patel, Vipulkumar %A Jin, Weihong %A Adam, Margaret P %A Baple, Emma L %A Dean, John %A Fong, Chin-To %A Hickey, Scott E %A Hudgins, Louanne %A Leon, Eyby %A Madan-Khetarpal, Suneeta %A Rawlins, Lettie %A Rustad, Cecilie F %A Stray-Pedersen, Asbjørg %A Tveten, Kristian %A Wenger, Olivia %A Diaz, Jullianne %A Jenkins, Laura %A Martin, Laura %A McGuire, Marianne %A Pietryga, Marguerite %A Ramsdell, Linda %A Slattery, Leah %A Abid, Farida %A Bertuch, Alison A %A Grange, Dorothy %A Immken, Ladonna %A Schaaf, Christian P %A Van Esch, Hilde %A Bi, Weimin %A Cheung, Sau Wai %A Breman, Amy M %A Smith, Janice L %A Shaw, Chad %A Crosby, Andrew H %A Christine M Eng %A Yang, Yaping %A James R Lupski %A Xiao, Rui %A Liu, Pengfei %K Adolescent %K Alleles %K Antigens, Nuclear %K Biological Variation, Population %K Carrier Proteins %K Cell Cycle Proteins %K Child %K Child, Preschool %K Chromosomal Proteins, Non-Histone %K Cohort Studies %K De Lange Syndrome %K Exome %K Female %K Gene Frequency %K Genetic Heterogeneity %K Humans %K INDEL Mutation %K Male %K Mutation %K Nuclear Proteins %K Phenotype %K Polymorphism, Single Nucleotide %K Proto-Oncogene Proteins %K Retrospective Studies %K Whole Exome Sequencing %X

PURPOSE: Defects in the cohesin pathway are associated with cohesinopathies, notably Cornelia de Lange syndrome (CdLS). We aimed to delineate pathogenic variants in known and candidate cohesinopathy genes from a clinical exome perspective.

METHODS: We retrospectively studied patients referred for clinical exome sequencing (CES, N = 10,698). Patients with causative variants in novel or recently described cohesinopathy genes were enrolled for phenotypic characterization.

RESULTS: Pathogenic or likely pathogenic single-nucleotide and insertion/deletion variants (SNVs/indels) were identified in established disease genes including NIPBL (N = 5), SMC1A (N = 14), SMC3 (N = 4), RAD21 (N = 2), and HDAC8 (N = 8). The phenotypes in this genetically defined cohort skew towards the mild end of CdLS spectrum as compared with phenotype-driven cohorts. Candidate or recently reported cohesinopathy genes were supported by de novo SNVs/indels in STAG1 (N = 3), STAG2 (N = 5), PDS5A (N = 1), and WAPL (N = 1), and one inherited SNV in PDS5A. We also identified copy-number deletions affecting STAG1 (two de novo, one of unknown inheritance) and STAG2 (one of unknown inheritance). Patients with STAG1 and STAG2 variants presented with overlapping features yet without characteristic facial features of CdLS.

CONCLUSION: CES effectively identified disease-causing alleles at the mild end of the cohensinopathy spectrum and enabled characterization of candidate disease genes.

%B Genet Med %V 21 %P 663-675 %8 2019 03 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/30158690?dopt=Abstract %R 10.1038/s41436-018-0085-6 %0 Journal Article %J N Engl J Med %D 2017 %T Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation. %A Posey, Jennifer E %A Harel, Tamar %A Liu, Pengfei %A Rosenfeld, Jill A %A James, Regis A %A Coban Akdemir, Zeynep H %A Walkiewicz, Magdalena %A Bi, Weimin %A Xiao, Rui %A Ding, Yan %A Xia, Fan %A Beaudet, Arthur L %A Muzny, Donna M %A Gibbs, Richard A %A Boerwinkle, Eric %A Eng, Christine M %A Sutton, V Reid %A Shaw, Chad A %A Plon, Sharon E %A Yang, Yaping %A Lupski, James R %K Exome %K Genetic Diseases, Inborn %K Genetic Variation %K Genotyping Techniques %K High-Throughput Nucleotide Sequencing %K Humans %K Phenotype %K Retrospective Studies %K Sequence Analysis, DNA %X

BACKGROUND: Whole-exome sequencing can provide insight into the relationship between observed clinical phenotypes and underlying genotypes.

METHODS: We conducted a retrospective analysis of data from a series of 7374 consecutive unrelated patients who had been referred to a clinical diagnostic laboratory for whole-exome sequencing; our goal was to determine the frequency and clinical characteristics of patients for whom more than one molecular diagnosis was reported. The phenotypic similarity between molecularly diagnosed pairs of diseases was calculated with the use of terms from the Human Phenotype Ontology.

RESULTS: A molecular diagnosis was rendered for 2076 of 7374 patients (28.2%); among these patients, 101 (4.9%) had diagnoses that involved two or more disease loci. We also analyzed parental samples, when available, and found that de novo variants accounted for 67.8% (61 of 90) of pathogenic variants in autosomal dominant disease genes and 51.7% (15 of 29) of pathogenic variants in X-linked disease genes; both variants were de novo in 44.7% (17 of 38) of patients with two monoallelic variants. Causal copy-number variants were found in 12 patients (11.9%) with multiple diagnoses. Phenotypic similarity scores were significantly lower among patients in whom the phenotype resulted from two distinct mendelian disorders that affected different organ systems (50 patients) than among patients with disorders that had overlapping phenotypic features (30 patients) (median score, 0.21 vs. 0.36; P=1.77×10).

CONCLUSIONS: In our study, we found multiple molecular diagnoses in 4.9% of cases in which whole-exome sequencing was informative. Our results show that structured clinical ontologies can be used to determine the degree of overlap between two mendelian diseases in the same patient; the diseases can be distinct or overlapping. Distinct disease phenotypes affect different organ systems, whereas overlapping disease phenotypes are more likely to be caused by two genes encoding proteins that interact within the same pathway. (Funded by the National Institutes of Health and the Ting Tsung and Wei Fong Chao Foundation.).

%B N Engl J Med %V 376 %P 21-31 %8 2017 Jan 05 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/27959697?dopt=Abstract %R 10.1056/NEJMoa1516767 %0 Journal Article %J JAMA Pediatr %D 2017 %T Use of Exome Sequencing for Infants in Intensive Care Units: Ascertainment of Severe Single-Gene Disorders and Effect on Medical Management. %A Meng, Linyan %A Pammi, Mohan %A Saronwala, Anirudh %A Magoulas, Pilar %A Ghazi, Andrew Ray %A Vetrini, Francesco %A Zhang, Jing %A He, Weimin %A Dharmadhikari, Avinash V %A Qu, Chunjing %A Ward, Patricia %A Braxton, Alicia %A Narayanan, Swetha %A Ge, Xiaoyan %A Tokita, Mari J %A Santiago-Sim, Teresa %A Dai, Hongzheng %A Chiang, Theodore %A Smith, Hadley %A Azamian, Mahshid S %A Robak, Laurie %A Bostwick, Bret L %A Schaaf, Christian P %A Potocki, Lorraine %A Scaglia, Fernando %A Bacino, Carlos A %A Hanchard, Neil A %A Wangler, Michael F %A Scott, Daryl %A Brown, Chester %A Hu, Jianhong %A Belmont, John W %A Burrage, Lindsay C %A Graham, Brett H %A Sutton, Vernon Reid %A Craigen, William J %A Plon, Sharon E %A Lupski, James R %A Beaudet, Arthur L %A Gibbs, Richard A %A Muzny, Donna M %A Miller, Marcus J %A Wang, Xia %A Leduc, Magalie S %A Xiao, Rui %A Liu, Pengfei %A Shaw, Chad %A Walkiewicz, Magdalena %A Bi, Weimin %A Xia, Fan %A Lee, Brendan %A Eng, Christine M %A Yang, Yaping %A Lalani, Seema R %K Adult %K Critical Care %K Disease Management %K Exome %K Exome Sequencing %K Genetic Counseling %K Genetic Diseases, Inborn %K Humans %K Infant %K Infant Care %K Infant, Newborn %K Intensive Care Units, Pediatric %K Length of Stay %K Retrospective Studies %K Texas %X

IMPORTANCE: While congenital malformations and genetic diseases are a leading cause of early infant death, to our knowledge, the contribution of single-gene disorders in this group is undetermined.

OBJECTIVE: To determine the diagnostic yield and use of clinical exome sequencing in critically ill infants.

DESIGN, SETTING, AND PARTICIPANTS: Clinical exome sequencing was performed for 278 unrelated infants within the first 100 days of life who were admitted to Texas Children's Hospital in Houston, Texas, during a 5-year period between December 2011 and January 2017. Exome sequencing types included proband exome, trio exome, and critical trio exome, a rapid genomic assay for seriously ill infants.

MAIN OUTCOMES AND MEASURES: Indications for testing, diagnostic yield of clinical exome sequencing, turnaround time, molecular findings, patient age at diagnosis, and effect on medical management among a group of critically ill infants who were suspected to have genetic disorders.

RESULTS: The mean (SEM) age for infants participating in the study was 28.5 (1.7) days; of these, the mean (SEM) age was 29.0 (2.2) days for infants undergoing proband exome sequencing, 31.5 (3.9) days for trio exome, and 22.7 (3.9) days for critical trio exome. Clinical indications for exome sequencing included a range of medical concerns. Overall, a molecular diagnosis was achieved in 102 infants (36.7%) by clinical exome sequencing, with relatively low yield for cardiovascular abnormalities. The diagnosis affected medical management for 53 infants (52.0%) and had a substantial effect on informed redirection of care, initiation of new subspecialist care, medication/dietary modifications, and furthering life-saving procedures in select patients. Critical trio exome sequencing revealed a molecular diagnosis in 32 of 63 infants (50.8%) at a mean (SEM) of 33.1 (5.6) days of life with a mean (SEM) turnaround time of 13.0 (0.4) days. Clinical care was altered by the diagnosis in 23 of 32 patients (71.9%). The diagnostic yield, patient age at diagnosis, and medical effect in the group that underwent critical trio exome sequencing were significantly different compared with the group who underwent regular exome testing. For deceased infants (n = 81), genetic disorders were molecularly diagnosed in 39 (48.1%) by exome sequencing, with implications for recurrence risk counseling.

CONCLUSIONS AND RELEVANCE: Exome sequencing is a powerful tool for the diagnostic evaluation of critically ill infants with suspected monogenic disorders in the neonatal and pediatric intensive care units and its use has a notable effect on clinical decision making.

%B JAMA Pediatr %V 171 %P e173438 %8 2017 Dec 04 %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/28973083?dopt=Abstract %R 10.1001/jamapediatrics.2017.3438