Publications by authors named "Jessica Sebastian"

14 Publications

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Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders.

Authors:
Madelyn A Gillentine Tianyun Wang Kendra Hoekzema Jill Rosenfeld Pengfei Liu Hui Guo Chang N Kim Bert B A De Vries Lisenka E L M Vissers Magnus Nordenskjold Malin Kvarnung Anna Lindstrand Ann Nordgren Jozef Gecz Maria Iascone Anna Cereda Agnese Scatigno Silvia Maitz Ginevra Zanni Enrico Bertini Christiane Zweier Sarah Schuhmann Antje Wiesener Micah Pepper Heena Panjwani Erin Torti Farida Abid Irina Anselm Siddharth Srivastava Paldeep Atwal Carlos A Bacino Gifty Bhat Katherine Cobian Lynne M Bird Jennifer Friedman Meredith S Wright Bert Callewaert Florence Petit Sophie Mathieu Alexandra Afenjar Celenie K Christensen Kerry M White Orly Elpeleg Itai Berger Edward J Espineli Christina Fagerberg Charlotte Brasch-Andersen Lars Kjærsgaard Hansen Timothy Feyma Susan Hughes Isabelle Thiffault Bonnie Sullivan Shuang Yan Kory Keller Boris Keren Cyril Mignot Frank Kooy Marije Meuwissen Alice Basinger Mary Kukolich Meredith Philips Lucia Ortega Margaret Drummond-Borg Mathilde Lauridsen Kristina Sorensen Anna Lehman Elena Lopez-Rangel Paul Levy Davor Lessel Timothy Lotze Suneeta Madan-Khetarpal Jessica Sebastian Jodie Vento Divya Vats L Manace Benman Shane Mckee Ghayda M Mirzaa Candace Muss John Pappas Hilde Peeters Corrado Romano Maurizio Elia Ornella Galesi Marleen E H Simon Koen L I van Gassen Kara Simpson Robert Stratton Sabeen Syed Julien Thevenon Irene Valenzuela Palafoll Antonio Vitobello Marie Bournez Laurence Faivre Kun Xia Rachel K Earl Tomasz Nowakowski Raphael A Bernier Evan E Eichler

Genome Med 2021 Apr 19;13(1):63. Epub 2021 Apr 19.

Department of Genome Sciences, University of Washington School of Medicine, 3720 15th Ave NE S413A, Box 355065, Seattle, WA, 981095-5065, USA.

Background: With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations.

Methods: We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk.

Results: We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs.

Conclusions: Overall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.
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http://dx.doi.org/10.1186/s13073-021-00870-6DOI Listing
April 2021

SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females.

Authors:
Francesca Clementina Radio Kaifang Pang Andrea Ciolfi Michael A Levy Andrés Hernández-García Lucia Pedace Francesca Pantaleoni Zhandong Liu Elke de Boer Adam Jackson Alessandro Bruselles Haley McConkey Emilia Stellacci Stefania Lo Cicero Marialetizia Motta Rosalba Carrozzo Maria Lisa Dentici Kirsty McWalter Megha Desai Kristin G Monaghan Aida Telegrafi Christophe Philippe Antonio Vitobello Margaret Au Katheryn Grand Pedro A Sanchez-Lara Joanne Baez Kristin Lindstrom Peggy Kulch Jessica Sebastian Suneeta Madan-Khetarpal Chelsea Roadhouse Jennifer J MacKenzie Berrin Monteleone Carol J Saunders July K Jean Cuevas Laura Cross Dihong Zhou Taila Hartley Sarah L Sawyer Fabíola Paoli Monteiro Tania Vertemati Secches Fernando Kok Laura E Schultz-Rogers Erica L Macke Eva Morava Eric W Klee Jennifer Kemppainen Maria Iascone Angelo Selicorni Romano Tenconi David J Amor Lynn Pais Lyndon Gallacher Peter D Turnpenny Karen Stals Sian Ellard Sara Cabet Gaetan Lesca Joset Pascal Katharina Steindl Sarit Ravid Karin Weiss Alison M R Castle Melissa T Carter Louisa Kalsner Bert B A de Vries Bregje W van Bon Marijke R Wevers Rolph Pfundt Alexander P A Stegmann Bronwyn Kerr Helen M Kingston Kate E Chandler Willow Sheehan Abdallah F Elias Deepali N Shinde Meghan C Towne Nathaniel H Robin Dana Goodloe Adeline Vanderver Omar Sherbini Krista Bluske R Tanner Hagelstrom Caterina Zanus Flavio Faletra Luciana Musante Evangeline C Kurtz-Nelson Rachel K Earl Britt-Marie Anderlid Gilles Morin Marjon van Slegtenhorst Karin E M Diderich Alice S Brooks Joost Gribnau Ruben G Boers Teresa Robert Finestra Lauren B Carter Anita Rauch Paolo Gasparini Kym M Boycott Tahsin Stefan Barakat John M Graham Laurence Faivre Siddharth Banka Tianyun Wang Evan E Eichler Manuela Priolo Bruno Dallapiccola Lisenka E L M Vissers Bekim Sadikovic Daryl A Scott Jimmy Lloyd Holder Marco Tartaglia

Am J Hum Genet 2021 03 16;108(3):502-516. Epub 2021 Feb 16.

Genetics and Rare Disease Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy. Electronic address:

Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.
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http://dx.doi.org/10.1016/j.ajhg.2021.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008487PMC
March 2021

Missense variants in CTNNB1 can be associated with vitreoretinopathy-Seven new cases of CTNNB1-associated neurodevelopmental disorder including a previously unreported retinal phenotype.

Mol Genet Genomic Med 2021 01 22;9(1):e1542. Epub 2020 Dec 22.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Background: CTNNB1 (MIM 116806) encodes beta-catenin, an adherens junction protein that supports the integrity between layers of epithelial tissue and mediates intercellular signaling. Recently, various heterozygous germline variants in CTNNB1 have been associated with human disease, including neurodevelopmental disorder with spastic diplegia and visual defects (MIM 615075) as well as isolated familial exudative vitreoretinopathy without developmental delays or other organ system involvement (MIM 617572). From over 40 previously reported patients with CTNNB1-related neurodevelopmental disorder, many have had ocular anomalies including strabismus, hyperopia, and astigmatism. More recently, multiple reports indicate that these abnormalities are associated with the presence of vitreoretinopathy.

Methods: We gathered a cohort of three patients with CTNNB1-related neurodevelopmental disorder, recruited from both our own clinic and referred from outside providers. We then searched for a clinical database comprised of over 12,000 exome sequencing studies to identify and recruit four additional patients.

Results: Here, we report seven new cases of CTNNB1-related neurodevelopmental disorder, all harboring de novo variants, six of which were previously unreported. All patients but one presented with a spectrum of ocular abnormalities and one patient, who was found to carry a missense variant in CTNNB1, had notable vitreoretinopathy.

Conclusions: Our findings suggest ophthalmologic screening should be performed in all patients with CTNNB1 variants.
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http://dx.doi.org/10.1002/mgg3.1542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963417PMC
January 2021

Ocular findings of albinism in related intellectual disability syndrome.

Ophthalmic Genet 2020 12 24;41(6):650-655. Epub 2020 Aug 24.

UPMC Eye Center , Pittsburgh, PA, USA.

Background: Pathogenic variants in are associated with -related intellectual disability syndrome (DIDS). Common features of this diagnosis include microcephaly, intellectual disability, speech impairment, and distinct facial features. Reported ocular features include deep-set eyes, myopia, and strabismus. We present a case of -related intellectual disability syndrome with ocular findings of albinism and explore the possible pathogenesis of this previously unreported manifestation.

Materials And Methods: This is a single, retrospective case report of a child with DIDS who underwent an ophthalmic exam including detailed visual electrophysiology. : A 21-month-old female with microcephaly, failure to thrive, language delay, cleft palate, and cardiac defects had an ophthalmic exam showing myopia, strabismus, a hypopigmented fundus and crossed asymmetry on visual evoked potential (VEP), consistent with ocular findings of albinism. Whole exome sequencing identified a pathogenic variant; no albinism gene variants were reported. Her constellation of features is consistent with a diagnosis of -related intellectual disability syndrome; however, ocular features of albinism have not previously been reported in this condition.

Conclusions: This is, to the best of our knowledge, the first report of ocular findings of albinism in a case of -related intellectual disability syndrome. We propose that ocular albinism is a novel ocular phenotype of -related disease. Ophthalmic exams in patients with this diagnosis should include thorough evaluation for ocular albinism, including VEPs.
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http://dx.doi.org/10.1080/13816810.2020.1814349DOI Listing
December 2020

Four children with postnatally diagnosed mosaic trisomy 12: Clinical features, literature review, and current diagnostic capabilities of genetic testing.

Am J Med Genet A 2020 04 8;182(4):813-822. Epub 2020 Jan 8.

Pittsburgh Cytogenetics Laboratory, UPMC Magee-Womens Hospital, Pittsburgh, Pennsylvania.

Children or adults with mosaic trisomy 12 diagnosed postnatally are extremely rare. Only a small number of patients with this mosaicism have been reported in the literature. The clinical manifestation of mosaic trisomy 12 is variable, ranging from mild developmental delay to severe congenital anomaly and neonatal death. The trisomy 12 cells are not usually able to be detected by phytohemagglutinin stimulated peripheral blood chromosome analysis. The variability of phenotypes and the limited number of patients with this anomaly pose a challenge to predict the clinical outcomes. In this study, we present the phenotypes and laboratory findings in four patients and review the 11 previously reported patients with mosaic trisomy 12 diagnosed postnatally, as well as 11 patients with mosaic trisomy 12 diagnosed prenatally. The findings of this study provide useful information for laboratory diagnosis and clinical management of these patients.
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http://dx.doi.org/10.1002/ajmg.a.61482DOI Listing
April 2020

Reticular Dysgenesis and Mitochondriopathy Induced by Adenylate Kinase 2 Deficiency with Atypical Presentation.

Sci Rep 2019 10 31;9(1):15739. Epub 2019 Oct 31.

Division of Medical Genetics, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA.

Reticular dysgenesis is an autosomal recessive form of severe combined immunodeficiency (SCID) that usually manifests in newborns. It is a unique example of an immune deficiency that is linked to dysfunctional mitochondrial energy metabolism and caused by adenylate kinase 2 (AK2) deficiency. It is characterized by an early differentiation arrest in the myeloid lineage, impaired lymphoid maturation, and sensorineural hearing loss. In this study, a novel AK2 homozygous mutation, c.622 T > C [p.Ser208Pro], was identified in an Old Order Amish patient through whole exome sequencing. Functional studies showed that the patient's cells have no detectable AK2 protein, as well as low oxygen consumption rate (OCR), extracellular acidification rate (ECAR) and proton production rate (PPR). An increased production of reactive oxygen species, mitochondrial membrane permeability, and mitochondrial mass, and decreased ATP production, were also observed. The results confirm the pathogenicity of the AK2 mutation and demonstrate that reticular dysgenesis should be considered in Amish individuals presenting with immune deficiency. We also describe other pathophysiological aspects of AK2 deficiency not previously reported.
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http://dx.doi.org/10.1038/s41598-019-51922-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823482PMC
October 2019

Disruptive variants of associate with autism and interfere with neuronal development and synaptic transmission.

Sci Adv 2019 09 25;5(9):eaax2166. Epub 2019 Sep 25.

Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.

RNA binding proteins are key players in posttranscriptional regulation and have been implicated in neurodevelopmental and neuropsychiatric disorders. Here, we report a significant burden of heterozygous, likely gene-disrupting variants in (encoding a highly constrained RNA binding protein) among patients with autism and related neurodevelopmental disabilities. Analysis of 17 patients identifies common phenotypes including autism, intellectual disability, language and motor delay, seizures, macrocephaly, and variable ocular abnormalities. HITS-CLIP revealed that Csde1-binding targets are enriched in autism-associated gene sets, especially FMRP targets, and in neuronal development and synaptic plasticity-related pathways. Csde1 knockdown in primary mouse cortical neurons leads to an overgrowth of the neurites and abnormal dendritic spine morphology/synapse formation and impaired synaptic transmission, whereas mutant and knockdown experiments in result in defects in synapse growth and synaptic transmission. Our study defines a new autism-related syndrome and highlights the functional role of CSDE1 in synapse development and synaptic transmission.
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http://dx.doi.org/10.1126/sciadv.aax2166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760934PMC
September 2019

Adverse Events in Genetic Testing: The Fourth Case Series.

Cancer J 2019 Jul/Aug;25(4):231-236

From the My Gene Counsel, LLC, Branford, CT.

Purpose: In this ongoing national case series, we document 25 new genetic testing cases in which tests were recommended, ordered, interpreted, or used incorrectly.

Methods: An invitation to submit cases of adverse events in genetic testing was issued to the general National Society of Genetic Counselors Listserv, the National Society of Genetic Counselors Cancer Special Interest Group members, private genetic counselor laboratory groups, and via social media platforms (i.e., Facebook, Twitter, LinkedIn). Examples highlighted in the invitation included errors in ordering, counseling, and/or interpretation of genetic testing and did not limit submissions to cases involving genetic testing for hereditary cancer predisposition. Clinical documentation, including pedigree, was requested. Twenty-six cases were accepted, and a thematic analysis was performed. Submitters were asked to approve the representation of their cases before manuscript submission.

Results: All submitted cases took place in the United States and were from cancer, pediatric, preconception, and general adult settings and involved both medical-grade and direct-to-consumer genetic testing with raw data analysis. In 8 cases, providers ordered the wrong genetic test. In 2 cases, multiple errors were made when genetic testing was ordered. In 3 cases, patients received incorrect information from providers because genetic test results were misinterpreted or because of limitations in the provider's knowledge of genetics. In 3 cases, pathogenic genetic variants identified were incorrectly assumed to completely explain the suspicious family histories of cancer. In 2 cases, patients received inadequate or no information with respect to genetic test results. In 2 cases, result interpretation/documentation by the testing laboratories was erroneous. In 2 cases, genetic counselors reinterpreted the results of people who had undergone direct-to-consumer genetic testing and/or clarifying medical-grade testing was ordered.

Discussion: As genetic testing continues to become more common and complex, it is clear that we must ensure that appropriate testing is ordered and that results are interpreted and used correctly. Access to certified genetic counselors continues to be an issue for some because of workforce limitations. Potential solutions involve action on multiple fronts: new genetic counseling delivery models, expanding the genetic counseling workforce, improving genetics and genomics education of nongenetics health care professionals, addressing health care policy barriers, and more. Genetic counselors have also positioned themselves in new roles to help patients and consumers as well as health care providers, systems, and payers adapt to new genetic testing technologies and models. The work to be done is significant, but so are the consequences of errors in genetic testing.
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http://dx.doi.org/10.1097/PPO.0000000000000391DOI Listing
July 2020

Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases.

Am J Hum Genet 2019 08 27;105(2):384-394. Epub 2019 Jun 27.

Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, QC H3T 1C5, Canada; Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine and University of Montreal, Montreal, QC H3T 1C5, Canada. Electronic address:

Proteins anchored to the cell surface via glycosylphosphatidylinositol (GPI) play various key roles in the human body, particularly in development and neurogenesis. As such, many developmental disorders are caused by mutations in genes involved in the GPI biosynthesis and remodeling pathway. We describe ten unrelated families with bi-allelic mutations in PIGB, a gene that encodes phosphatidylinositol glycan class B, which transfers the third mannose to the GPI. Ten different PIGB variants were found in these individuals. Flow cytometric analysis of blood cells and fibroblasts from the affected individuals showed decreased cell surface presence of GPI-anchored proteins. Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy. Eight children passed away before four years old. Two of them had a clinical diagnosis of DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures), a condition that includes sensorineural deafness, shortened terminal phalanges with small finger and toenails, intellectual disability, and seizures; this condition overlaps with the severe phenotypes associated with inherited GPI deficiency. Most individuals tested showed elevated alkaline phosphatase, which is a characteristic of the inherited GPI deficiency but not DOORS syndrome. It is notable that two severely affected individuals showed 2-oxoglutaric aciduria, which can be seen in DOORS syndrome, suggesting that severe cases of inherited GPI deficiency and DOORS syndrome might share some molecular pathway disruptions.
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http://dx.doi.org/10.1016/j.ajhg.2019.05.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698938PMC
August 2019

Mutations in ACTL6B Cause Neurodevelopmental Deficits and Epilepsy and Lead to Loss of Dendrites in Human Neurons.

Am J Hum Genet 2019 05 25;104(5):815-834. Epub 2019 Apr 25.

CHU-Sainte Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada. Electronic address:

We identified individuals with variations in ACTL6B, a component of the chromatin remodeling machinery including the BAF complex. Ten individuals harbored bi-allelic mutations and presented with global developmental delay, epileptic encephalopathy, and spasticity, and ten individuals with de novo heterozygous mutations displayed intellectual disability, ambulation deficits, severe language impairment, hypotonia, Rett-like stereotypies, and minor facial dysmorphisms (wide mouth, diastema, bulbous nose). Nine of these ten unrelated individuals had the identical de novo c.1027G>A (p.Gly343Arg) mutation. Human-derived neurons were generated that recaptured ACTL6B expression patterns in development from progenitor cell to post-mitotic neuron, validating the use of this model. Engineered knock-out of ACTL6B in wild-type human neurons resulted in profound deficits in dendrite development, a result recapitulated in two individuals with different bi-allelic mutations, and reversed on clonal genetic repair or exogenous expression of ACTL6B. Whole-transcriptome analyses and whole-genomic profiling of the BAF complex in wild-type and bi-allelic mutant ACTL6B neural progenitor cells and neurons revealed increased genomic binding of the BAF complex in ACTL6B mutants, with corresponding transcriptional changes in several genes including TPPP and FSCN1, suggesting that altered regulation of some cytoskeletal genes contribute to altered dendrite development. Assessment of bi-alleic and heterozygous ACTL6B mutations on an ACTL6B knock-out human background demonstrated that bi-allelic mutations mimic engineered deletion deficits while heterozygous mutations do not, suggesting that the former are loss of function and the latter are gain of function. These results reveal a role for ACTL6B in neurodevelopment and implicate another component of chromatin remodeling machinery in brain disease.
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http://dx.doi.org/10.1016/j.ajhg.2019.03.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6507050PMC
May 2019

Expanding the Spectrum of BAF-Related Disorders: De Novo Variants in SMARCC2 Cause a Syndrome with Intellectual Disability and Developmental Delay.

Am J Hum Genet 2019 01 20;104(1):164-178. Epub 2018 Dec 20.

Department of Pediatrics, CHU Sainte-Justine Research Center and University of Montreal, Montreal, QC H3T 1C5, Canada. Electronic address:

SMARCC2 (BAF170) is one of the invariable core subunits of the ATP-dependent chromatin remodeling BAF (BRG1-associated factor) complex and plays a crucial role in embryogenesis and corticogenesis. Pathogenic variants in genes encoding other components of the BAF complex have been associated with intellectual disability syndromes. Despite its significant biological role, variants in SMARCC2 have not been directly associated with human disease previously. Using whole-exome sequencing and a web-based gene-matching program, we identified 15 individuals with variable degrees of neurodevelopmental delay and growth retardation harboring one of 13 heterozygous variants in SMARCC2, most of them novel and proven de novo. The clinical presentation overlaps with intellectual disability syndromes associated with other BAF subunits, such as Coffin-Siris and Nicolaides-Baraitser syndromes and includes prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features such as hypertrichosis, thick eyebrows, thin upper lip vermilion, and upturned nose. Nine out of the fifteen individuals harbor variants in the highly conserved SMARCC2 DNA-interacting domains (SANT and SWIRM) and present with a more severe phenotype. Two of these individuals present cardiac abnormalities. Transcriptomic analysis of fibroblasts from affected individuals highlights a group of differentially expressed genes with possible roles in regulation of neuronal development and function, namely H19, SCRG1, RELN, and CACNB4. Our findings suggest a novel SMARCC2-related syndrome that overlaps with neurodevelopmental disorders associated with variants in BAF-complex subunits.
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http://dx.doi.org/10.1016/j.ajhg.2018.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323608PMC
January 2019

Familial deletion of the HOXA gene cluster associated with Hand-Foot-Genital syndrome and phenotypic variability.

Am J Med Genet A 2017 Jan 20;173(1):221-224. Epub 2016 Sep 20.

Pediatric Endocrinology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania.

Hand-Foot-Genital syndrome is a rare autosomal dominant condition characterized by distal limb anomalies and urogenital malformations. This disorder is associated with loss-of-function mutations in the HOXA13 gene. HOXA13 plays an important role in the development of distal limbs and lower genitourinary tract of the fetus. We report a novel familial 589 kb deletion in the 7p15.2 region identified in a male toddler and his mother. The proband had severe penoscrotal hypospadias, mild skeletal anomalies of the hands and feet, cardiac, renal, and gastrointestinal anomalies. His mother had a bicornuate uterus, cervical incompetence, and minor anomalies of her hands and feet. This family was found to have the smallest reported deletion of 7p15.2 to date, and presented with features typical of Hand-Foot-Genital syndrome in the mother, but much more severe phenotype in her son. This deletion included the entire HOXA cluster in addition to the SKAP2 and EVX1 genes. An RT-PCR analysis was performed to determine the expression of the HOXA genes in the proband and to explore a parent-of-origin effect. Our expression studies did not support the hypothesis of an imprinted status of the HOXA2, HOXA3, HOXA5, and HOXA11 genes in peripheral blood. To our knowledge, this is the first familial 7p15.2 deletion. This family raises possibility for sexual dimorphism as a mechanism for phenotypic variability in patients with the HOXA gene cluster deletions. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.37981DOI Listing
January 2017

Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins.

Authors:
Przemyslaw Szafranski Tomasz Gambin Avinash V Dharmadhikari Kadir Caner Akdemir Shalini N Jhangiani Jennifer Schuette Nihal Godiwala Svetlana A Yatsenko Jessica Sebastian Suneeta Madan-Khetarpal Urvashi Surti Rosanna G Abellar David A Bateman Ashley L Wilson Melinda H Markham Jill Slamon Fernando Santos-Simarro María Palomares Julián Nevado Pablo Lapunzina Brian Hon-Yin Chung Wai-Lap Wong Yoyo Wing Yiu Chu Gary Tsz Kin Mok Eitan Kerem Joel Reiter Namasivayam Ambalavanan Scott A Anderson David R Kelly Joseph Shieh Taryn C Rosenthal Kristin Scheible Laurie Steiner M Anwar Iqbal Margaret L McKinnon Sara Jane Hamilton Kamilla Schlade-Bartusiak Dawn English Glenda Hendson Elizabeth R Roeder Thomas S DeNapoli Rebecca Okashah Littlejohn Daynna J Wolff Carol L Wagner Alison Yeung David Francis Elizabeth K Fiorino Morris Edelman Joyce Fox Denise A Hayes Sandra Janssens Elfride De Baere Björn Menten Anne Loccufier Lieve Vanwalleghem Philippe Moerman Yves Sznajer Amy S Lay Jennifer L Kussmann Jasneek Chawla Diane J Payton Gael E Phillips Erwin Brosens Dick Tibboel Annelies de Klein Isabelle Maystadt Richard Fisher Neil Sebire Alison Male Maya Chopra Jason Pinner Girvan Malcolm Gregory Peters Susan Arbuckle Melissa Lees Zoe Mead Oliver Quarrell Richard Sayers Martina Owens Charles Shaw-Smith Janet Lioy Eileen McKay Nicole de Leeuw Ilse Feenstra Liesbeth Spruijt Frances Elmslie Timothy Thiruchelvam Carlos A Bacino Claire Langston James R Lupski Partha Sen Edwina Popek Paweł Stankiewicz

Hum Genet 2016 May 12;135(5):569-586. Epub 2016 Apr 12.

Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Rm. R809, Houston, TX, 77030, USA.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV.
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http://dx.doi.org/10.1007/s00439-016-1655-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5518754PMC
May 2016

CNTN6 copy number variations in 14 patients: a possible candidate gene for neurodevelopmental and neuropsychiatric disorders.

J Neurodev Disord 2015 6;7(1):26. Epub 2015 Aug 6.

Pittsburgh Cytogenetics Laboratory, Center of Medical Genetics and Genomics, Magee-Womens Hospital of UPMC, Pittsburgh, PA 15213 USA ; Department of Obstetrics, Gynecology & Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 USA ; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 USA.

Background: Neurodevelopmental disorders are impairments of brain function that affect emotion, learning, and memory. Copy number variations of contactin genes (CNTNs), including CNTN3, CNTN4, CNTN5, and CNTN6, have been suggested to be associated with these disorders. However, phenotypes have been reported in only a handful of patients with copy number variations involving CNTNs.

Methods: From January 2009 to January 2013, 3724 patients ascertained through the University of Pittsburgh Medical Center were referred to our laboratory for clinical array comparative genomic hybridization testing. We screened this cohort of patients to identify individuals with the 3p26.3 copy number variations involving the CNTN6 gene, and then retrospectively reviewed the clinical information and family history of these patients to determine the association between the 3p26.3 copy number variations and neurodevelopmental disorders.

Results: Fourteen of the 3724 patients had 3p26.3 copy number variations involving the CNTN6 gene. Thirteen of the 14 patients with these CNTN6 copy number variations presented with various neurodevelopmental disorders including developmental delay, autistic spectrum disorders, seizures and attention deficit hyperactivity disorder. Family history was available for 13 of the 14 patients. Twelve of the thirteen families have multiple members with neurodevelopmental and neuropsychiatric disorders including attention deficit hyperactivity disorder, seizures, autism spectrum disorder, intellectual disability, schizophrenia, depression, anxiety, learning disability, and bipolar disorder.

Conclusions: Our findings suggest that deletion or duplication of the CNTN6 gene is associated with a wide spectrum of neurodevelopmental behavioral disorders.
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http://dx.doi.org/10.1186/s11689-015-9122-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4528395PMC
August 2015