Publications by authors named "Ina Amarillo"

21 Publications

  • Page 1 of 1

Confirmation of Xp22.11 Duplication as a Germline Susceptibility Alteration in a Wilms Tumor Arising in Horseshoe Kidney.

Fetal Pediatr Pathol 2021 May 7:1-6. Epub 2021 May 7.

The Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.

Background: There is strong evidence of a genetic contribution to Wilms tumor, such as gene variation or epigenetic changes at chromosome locus 11p15. A previous genome wide association study (GWAS) of Wilms tumor identified other significant association loci including Xp22. A 4-year-old girl developed a Wilms tumor of the left isthmus of a horseshoe kidney. Chromosomal microarray analysis (CMA) of peripheral blood showed a 563 kb copy number gain at Xp22.11 that included . has been shown to play an active role in the tumorigenesis of malignant neoplasms in various organs. Beckwith-Wiedemann methylation analysis and sequencing were negative. Whole exome sequencing of peripheral blood revealed pathogenic variant in gene (c.765C > A), which is consistent with Lynch syndrome. We report a case of Wilms tumor with germline Xp22.11 duplication which further supports this locus as germline susceptibility alteration for Wilms Tumor.
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http://dx.doi.org/10.1080/15513815.2021.1921892DOI Listing
May 2021

Pathogenic paternally inherited NLGN4X deletion in a female with autism spectrum disorder: Clinical, cytogenetic, and molecular characterization.

Am J Med Genet A 2021 03 24;185(3):894-900. Epub 2020 Dec 24.

Department of Pathology and Laboratory Medicine, UCLA Clinical Genomics Center, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, California, USA.

Neuroligin 4 X-linked (NLGN4X) is an X-linked postsynaptic scaffolding protein, with functional role in excitatory synapsis development and maintenance, that has been associated with neuropsychiatric disorders such as intellectual disability, autism spectrum disorders (ASD), anxiety, attention deficit hyperactivity disorder (ADHD), and Tourette's syndrome. Chromosomal microarray analysis identified a paternally inherited, 445 Kb deletion on Xp22.3 that includes the entire NLGN4X in a 2.5 year old female (46,XX) with congenital hypotonia, strabismus, ASD, and increased aggressive behavioral issues. Her family history is significant for a mother with learning disabilities, a father with anxiety, major depressive disorder, and substance abuse, as well as two maternal half-brothers with developmental delays. X-inactivation studies in the proband's blood showed random X-inactivation despite the presence of an abnormal X chromosome. Furthermore, trio exome sequencing did not reveal any other deleterious variant that could explain her phenotype. Our report describes the first example of a paternally inherited NLGN4X microdeletion as the genetic etiology of ASD in a female proband, and the psychiatric phenotypes in the father. It also provides further evidence that NLGN4X is sensitive to dosage changes in females, and can contribute to a variety of psychiatric features within the same family.
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http://dx.doi.org/10.1002/ajmg.a.62025DOI Listing
March 2021

Creating Affirmative and Inclusive Practices When Providing Genetic and Genomic Diagnostic and Research Services to Gender-Expansive and Transgender Patients.

J Appl Lab Med 2021 Jan;6(1):142-154

Division of Laboratory and Genomic Medicine, Department of Pathology and Immunology, Washington University School of Medicine in Saint Louis, MO.

Background: Gender expansive and transgender (GET) healthcare extends beyond gender-affirming therapies, reaching every medical specialty and subspecialty. As the number of GET patients seeking health services has increased, so has the need for standards of care regarding GET-affirmative practices throughout the healthcare system. As such, the number of publications surrounding GET-affirmative practices has steadily risen. However, even as such research has gained ground in other areas, one realm in which there has been a relative lag is genetics and genomics (GG).

Content: In this article, we track the GET patient and their laboratory sample from the clinic to the GG laboratory and back. Throughout the preanalytical, analytical, and postanalytical phases, we identify publications, recommendations, and guidelines relevant to the care of the GET community. We also identity knowledge gaps in each area and provide recommendations for affirmative and inclusive processes for addressing those gaps.

Summary: We have identified the practices involved in GG services that would benefit from GET-affirmative process improvement, reviewing relevant affirmative guidelines. Where guidelines could not be found, we identified those knowledge gaps and suggested potential solutions and future directions for implementing GET-affirmative practices.
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http://dx.doi.org/10.1093/jalm/jfaa165DOI Listing
January 2021

Delineation of the 1q24.3 microdeletion syndrome provides further evidence for the potential role of non-coding RNAs in regulating the skeletal phenotype.

Bone 2021 01 22;142:115705. Epub 2020 Oct 22.

Department of Pediatrics, Division of Medical Genetics, Washington University School of Medicine, St. Louis, MO, USA. Electronic address:

Microdeletions within 1q24 have been associated with growth deficiency, varying intellectual disability, and skeletal abnormalities. The candidate locus responsible for the various phenotypic features of this syndrome has previously been predicted to lie in the area of 1q24.3, but molecular evidence of the causative gene remains elusive. Here, we report two additional patients carrying the smallest reported 1q24 deletion to date. Patient 1 exhibited intrauterine growth retardation, shortening of the long bones, frontal bossing, microstomia, micrognathia, and a language acquisition delay. Her mother, Patient 2, displayed a broad forehead and nasal bridge, thick supraorbital ridges, and toe brachydactyly, along with learning disability and language acquisition delay. The microdeletion encompasses a 94 Kb region containing exon 14 and portions of the surrounding introns of the gene encoding dynamin 3 (DNM3), resulting in an in-frame loss of 38 amino acids. This microdeletion site also contains a long non-coding RNA (DNM3OS) and three microRNAs (miR-214, miR-199A2, and miR-3120). Following culture of patient-derived and control fibroblasts, molecular analyses were performed to determine expression levels of genes affected by the heterozygous deletion. Results show decreased expression of DNM3OS and miR-214-3p in patient fibroblasts cultured in an osteogenic induction medium. Overall, our data provide further evidence to support a functional role for non-coding RNAs in regulating the skeletal phenotype, and the potential of a functionally-impaired DNM3 protein causing the non-skeletal disease pathogenesis.
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http://dx.doi.org/10.1016/j.bone.2020.115705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020873PMC
January 2021

Rare and duplications containing in clubfoot.

J Med Genet 2020 12 9;57(12):851-857. Epub 2020 Jun 9.

Department of Neurology, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri, USA

Introduction: Congenital clubfoot is a common birth defect that affects at least 0.1% of all births. Nearly 25% cases are familial and the remaining are sporadic in inheritance. Copy number variants (CNVs) involving transcriptional regulators of limb development, including and , have previously been shown to cause familial clubfoot, but much of the heritability remains unexplained.

Methods: Exome sequence data from 816 unrelated clubfoot cases and 2645 in-house controls were analysed using coverage data to identify rare CNVs. The precise size and location of duplications were then determined using high-density Affymetrix Cytoscan chromosomal microarray (CMA). Segregation in families and status were determined using qantitative PCR.

Results: Chromosome Xp22.33 duplications involving were identified in 1.1% of cases (9/816) compared with 0.07% of in-house controls (2/2645) (p=7.98×10, OR=14.57) and 0.27% (38/13592) of Atherosclerosis Risk in Communities/the Wellcome Trust Case Control Consortium 2 controls (p=0.001, OR=3.97). CMA validation confirmed an overlapping 180.28 kb duplicated region that included exons as well as downstream non-coding regions. In four of six sporadic cases where DNA was available for unaffected parents, the duplication was . The probability of four mutations in by chance in a cohort of 450 sporadic clubfoot cases is 5.4×10.

Conclusions: Microduplications of the pseudoautosomal chromosome Xp22.33 region (PAR1) containing and downstream enhancer elements occur in ~1% of patients with clubfoot. and regulatory regions have previously been implicated in skeletal dysplasia as well as idiopathic short stature, but have not yet been reported in clubfoot. duplications likely contribute to clubfoot pathogenesis by altering early limb development.
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http://dx.doi.org/10.1136/jmedgenet-2020-106842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688552PMC
December 2020

Intragenic CNTN4 copy number variants associated with a spectrum of neurobehavioral phenotypes.

Eur J Med Genet 2020 Mar 15;63(3):103736. Epub 2019 Aug 15.

Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA. Electronic address:

Deletions and duplications involving the CNTN4 gene, which encodes for the contactin 4 protein, have been reported in children with autism spectrum disorder (ASD) and other neurodevelopmental phenotypes. In this study, we performed clinical and genetic characterization of three individuals from unrelated families with copy number variants (CNV) (one deletion and two duplications) within CNTN4. The patients exhibited cognitive delay (3/3), growth restriction (3/3), motor delay (2/3), and febrile seizure/epilepsy (2/3). In contrast to previous reports, all probands presented with speech apraxia or delay with no diagnosis of ASD. Parental studies for the proband with the deletion and one of the 2 probands with the duplication revealed paternal origin of the CNTN4 CNV. Interestingly, previously documented CNV involving this gene were mostly inherited from unaffected fathers, raising questions regarding reduced penetrance and potential parent-of-origin effect. Our findings are compared with previously reported patients and patients in the DECIPHER database. The speech impairment in the three probands suggests a role for CNTN4 in language development. We discuss potential factors contributing to phenotypic heterogeneity and reduced penetrance and attempt to find possible genotype-phenotype correlation. Larger cohorts are needed for comprehensive and unbiased phenotyping and molecular characterization that may lead to better understanding of the underlying mechanisms of reduced penetrance, variable expressivity, and potential parent-of-origin effect of copy number variants encompassing CNTN4.
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http://dx.doi.org/10.1016/j.ejmg.2019.103736DOI Listing
March 2020

Distal chromosome 16p11.2 duplications containing in patients with scoliosis.

J Med Genet 2019 07 25;56(7):427-433. Epub 2019 Feb 25.

Department of Neurology, Division of Pediatric Neurology, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA.

Introduction: Adolescent idiopathic scoliosis (AIS) is a common musculoskeletal disorder with strong evidence for a genetic contribution. CNVs play an important role in congenital scoliosis, but their role in idiopathic scoliosis has been largely unexplored.

Methods: Exome sequence data from 1197 AIS cases and 1664 in-house controls was analysed using coverage data to identify rare CNVs. CNV calls were filtered to include only highly confident CNVs with >10 average reads per region and mean log-ratio of coverage consistent with single-copy duplication or deletion. The frequency of 55 common recurrent CNVs was determined and correlated with clinical characteristics.

Results: Distal chromosome 16p11.2 microduplications containing the gene were found in 0.7% of AIS cases (8/1197). We replicated this finding in two additional AIS cohorts (8/1097 and 2/433), resulting in 0.7% (18/2727) of all AIS cases harbouring a chromosome 16p11.2 microduplication, compared with 0.06% of local controls (1/1664) and 0.04% of published controls (8/19584) (p=2.28×10, OR=16.15). Furthermore, examination of electronic health records of 92 455 patients from the Geisinger health system showed scoliosis in 30% (20/66) patients with chromosome 16p11.2 microduplications containing compared with 7.6% (10/132) of controls (p=5.6×10, OR=3.9).

Conclusions: Recurrent distal chromosome 16p11.2 duplications explain nearly 1% of AIS. Distal chromosome 16p11.2 duplications may contribute to scoliosis pathogenesis by directly impairing growth or by altering expression of nearby genes, such as . Individuals with distal chromosome 16p11.2 microduplications should be screened for scoliosis to facilitate early treatment.
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http://dx.doi.org/10.1136/jmedgenet-2018-105877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592771PMC
July 2019

Inherited Deletion of 1q, Hyperparathyroidism and Signs of Y-chromosomal Influence in a Patient with Turner Syndrome

J Clin Res Pediatr Endocrinol 2019 02 9;11(1):88-93. Epub 2018 May 9.

Washington University Faculty of Medicine, Department of Pediatrics, Washington, USA

We report a detailed phenotypic, cytogenetic and molecular characterization of a patient prenatally diagnosed with Turner syndrome (TS). In addition to having typical TS clinical characteristics including webbed neck, high arched palate and coarctation of the aorta, the patient had features less frequently seen in TS. These included recurrent parathyroid adenomas, growth along the 75-90 centiles on the TS height curve despite minimal treatment with growth hormone, behavioral problems and evidence of gonadal dysgenesis with testicular-like structures, such as seminiferous tubules lined by Sertoli cells and a contiguous nodule of Leydig cells. While fluorescence hybridization (FISH) failed to detect Y-chromosome material in gonadal tissue or blood samples, chromosomal microarray analysis (CMA) confirmed X monosomy and a 4.69 Mb copy number loss on 1q31.2q31.3 (bp 192,715,814 to 197,401,180). This region contains the gene which has been associated with hyperparathyroidism-jaw tumor syndrome, features of which include recurrent, functional parathyroid adenomas and behavioral issues. This case illustrates how atypical features in a TS patient, such as robust growth and recurrent parathyroid adenomas, may suggest an underlying molecular etiology that should be explored by additional genetic diagnostic modalities. It is therefore appropriate in such cases to conduct further genetic testing, such as CMA and FISH, to explore other diagnostic possibilities and possibly prevent further complications.
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http://dx.doi.org/10.4274/jcrpe.galenos.2018.2018.0005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398186PMC
February 2019

Acute graft-versus-host disease following lung transplantation in a patient with a novel mutation.

Thorax 2018 05 30;73(5):489-492. Epub 2018 Jan 30.

Division of Hematology, Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, USA.

Familial pulmonary fibrosis is associated with loss-of-function mutations in telomerase reverse transcriptase () and short telomeres. Interstitial lung diseases have become the leading indication for lung transplantation in the USA, and recent data indicate that pathogenic mutations in telomerase may cause unfavourable outcomes following lung transplantation. Although a rare occurrence, solid organ transplant recipients who develop acute graft-versus-host disease (GVHD) have very poor survival. This case report describes the detection of a novel mutation in in a patient who had lung transplantation for familial pulmonary fibrosis and died from complications of acute GVHD.
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http://dx.doi.org/10.1136/thoraxjnl-2017-211121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5972828PMC
May 2018

Risk association of congenital anomalies in patients with ambiguous genitalia: A 22-year single-center experience.

J Pediatr Urol 2018 04 20;14(2):153.e1-153.e7. Epub 2017 Nov 20.

Division of Laboratory and Genomic Medicine, Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St Louis, MO, USA. Electronic address:

Background: Ambiguous genitalia refers to a form of differences of sex development (DSD) wherein the appearance of the external genitalia is atypical. This rare condition presents challenges in decision-making and clinical management. Review of historical data may reveal areas for clinical research to improve care for patients with ambiguous genitalia.

Objective: This chart review was performed to identify patients with ambiguous genitalia, and to classify them as having 46,XX DSD, 46,XY DSD, or sex chromosome DSD. Within these categories, we looked at establishment of specific diagnoses, type and frequency of other congenital anomalies and neoplasms, and gender assignment, as well as incidence of gender reassignment and transition.

Methods: We performed a retrospective chart review of patients diagnosed with DSD conditions from 1995 to 2016 using ICD9 codes. For the purpose of this study, review was limited to individuals assessed to have neonatal "ambiguous genitalia" or "indeterminate sex."

Results: Review identified 128 patients evaluated for ambiguous genitalia from 22 years of experience (Figure). Approximately half of these (53%) had 46,XY karyotype, 35% had 46,XX, and the remaining 12% had sex chromosome aberrations. Diagnostic rate for 46,XX DSD was higher at 64%, all of which were congenital adrenal hyperplasia, while diagnostic rate for 46,XY DSD was 11.7% for a molecularly confirmed diagnosis and 24% if clinical diagnoses were included. The most common anomalies included cardiac anomalies in 28/128 (22%), skeletal anomalies in 19/128 (15%), and failure to thrive or growth problems in 19/128 (15%). Additional congenital anomalies were found in 53 out of 128 patients (41%). There were three reported neoplasms in this group: gonadoblastoma, hepatoblastoma, and myelodysplastic syndrome with monosomy 7. Gender assignment was consistent with chromosomes in approximately 90% of XX and XY patients. There were three recorded gender reassignments or transitions.

Discussion: Diagnostic rate for ambiguous genitalia is low, especially in 46,XY DSD. Most neonates were assigned gender consistent with their chromosomes. Given the high rate of associated anomalies, screening for cardiac or other anomalies in patients with ambiguous genitalia may be beneficial.

Conclusion: Patients with ambiguous genitalia often have additional congenital anomalies. Establishment of a specific diagnosis is uncommon in 46,XY patients. A few patients have gender reassignment outside of the newborn period. Ongoing collection of clinical data on this population may reveal new information regarding long-term health, quality of life, and establishment of more diagnoses with improved molecular techniques.
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http://dx.doi.org/10.1016/j.jpurol.2017.09.027DOI Listing
April 2018

Mixed Donor Chimerism Following Simultaneous Pancreas-Kidney Transplant.

Exp Clin Transplant 2018 Jun 28;16(3):307-313. Epub 2017 Jun 28.

U.O.C. Division of Immunohematology, Transfusion Medicine and Transplant Immunology, Regional Reference Laboratory of Transplant Immunology, Azienda Ospedaliera Universitaria, Second University of Naples, Naples, Italy.

Objectives: Graft-versus-host disease after solid-organ transplant is exceedingly rare. Although the precise pathogenetic mechanisms are unknown, a progressive increase in donor chimerism is a requirement for its development. The incidence of mixed donor chimerism and its timeline after simultaneous pancreas-kidney transplant is unknown.

Materials And Methods: After encountering 2 cases of graft-versus-host disease after simultaneous pancreas-kidney transplant at our institution over a period of < 2 years, a collaborative pilot study was conducted by the bone marrow transplant, nephrology, and abdominal transplant surgery teams. We enrolled all consecutive patients undergoing sex-mismatched simultaneous pancreas-kidney transplant over 1 year and longitudinally monitored donor chimerism using fluorescence in situ hybridization for sex chromosomes.

Results: We found no evidence for chimerism in our 7 patients. In a comprehensive literature review, we found a total of 25 previously reported cases of graft-versus-host disease after kidney, pancreas, and simultaneous pancreas-kidney transplants. The median onset of graft-versus-host disease was approximately 5 weeks after transplant, with a median of about 2 weeks of delay between first presentation and diagnosis. Skin, gut, and bone marrow were almost equally affected at initial presentation, and fever of unknown origin occurred in more than half of patients. The median survival measured from the first manifestation of graft-versus-host disease was only 48 days.

Conclusions: Within the limitations related to small sample size, our results argue against an unusually high risk of graft-versus-host disease after simultaneous pancreas-kidney transplant. Collaboration between solid-organ and stem cell transplant investigators can be fruitful and can improve our understanding of the complications that are shared between the 2 fields.
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http://dx.doi.org/10.6002/ect.2016.0299DOI Listing
June 2018

Small copy-number variations involving genes of the FGF pathway in differences in sex development.

Hum Genome Var 2017 13;4:17011. Epub 2017 Apr 13.

Cytogenetics and Molecular Pathology Laboratory, Division of Laboratory and Genomic Medicine, Department of Pathology and Immunology, Washington University in St Louis School of Medicine, Saint Louis, MO, USA.

Retrospective chromosome microarray analysis of 83 genes within the fibroblast growth factor signaling pathway in 52 patients with heterogeneous differences in sex development (DSD) revealed small copy-number variations (CNVs) in ~31% (=26) of investigated genes. Roughly half of these genes (39/83) are ⩽50 kb. This study highlights the potential involvement of small CNVs in disrupting normal gene function and dysregulating genes of the FGF pathway associated with DSD.
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http://dx.doi.org/10.1038/hgv.2017.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5390097PMC
April 2017

Integrated small copy number variations and epigenome maps of disorders of sex development.

Hum Genome Var 2016 9;3:16012. Epub 2016 Jun 9.

Department of Genetics, Washington University in St Louis School of Medicine , St Louis, MO, USA.

Small copy number variations (CNVs) have typically not been analyzed or reported in clinical settings and hence have remained underrepresented in databases and the literature. Here, we focused our investigations on these small CNVs using chromosome microarray analysis (CMA) data previously obtained from patients with atypical characteristics or disorders of sex development (DSD). Using our customized CMA track targeting 334 genes involved in the development of urogenital and reproductive structures and a less stringent analysis filter, we uncovered small genes with recurrent and overlapping CNVs as small as 1 kb, and small regions of homozygosity (ROHs), imprinting and position effects. Detailed analysis of these high-resolution data revealed CNVs and ROHs involving structural and functional domains, repeat elements, active transcription sites and regulatory regions. Integration of these genomic data with DNA methylation, histone modification and predicted RNA expression profiles in normal testes and ovaries suggested spatiotemporal and tissue-specific gene regulation. This study emphasized a DSD-specific and gene-targeted CMA approach that uncovered previously unanalyzed or unreported small genes and CNVs, contributing to the growing resources on small CNVs and facilitating the narrowing of the genomic gap for identifying candidate genes or regions. This high-resolution analysis tool could improve the diagnostic utility of CMA, not only in patients with DSD but also in other clinical populations. These integrated data provided a better genomic-epigenomic landscape of DSD and greater opportunities for downstream research.
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http://dx.doi.org/10.1038/hgv.2016.12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899613PMC
June 2016

De novo 9q gain in an infant with tetralogy of Fallot with absent pulmonary valve: Patient report and review of congenital heart disease in 9q duplication syndrome.

Am J Med Genet A 2015 Dec 19;167A(12):2966-74. Epub 2015 Aug 19.

Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, Missouri.

Genomic disruptions, altered epigenetic mechanisms, and environmental factors contribute to the heterogeneity of congenital heart defects (CHD). In recent years, chromosomal microarray analysis (CMA) has led to the identification of numerous copy number variations (CNV) in patients with CHD. Genes disrupted by and within these CNVs thus represent excellent candidate genes for CHD. Microduplications of 9q (9q+) have been described in patients with CHD, however, the critical gene locus remains undetermined. Here we discuss an infant with tetralogy of Fallot with absent pulmonary valve, fetal hydrops, and a 3.76 Mb de novo contiguous gain of 9q34.2-q34.3 detected by CMA, and confirmed by karyotype and FISH studies. This duplicated interval disrupted RXRA (retinoid X receptor alpha; OMIM #180245) at intron 1. We also review CHD findings among previously reported patients with 9q (9q+) duplication syndrome. This is the first report implicating RXRA in CHD with 9q duplication, providing additional data in understanding the genetic etiology of tetralogy of Fallot, CHD, and disorders linked to 9q microduplication syndrome. This report also highlights the significance of CMA in the clinical diagnosis and genetic counseling of patients and families with complex CHD.
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http://dx.doi.org/10.1002/ajmg.a.37296DOI Listing
December 2015

BRCA2-associated therapy-related acute myeloid leukemia.

Med Oncol 2015 Jan 27;32(1):371. Epub 2014 Nov 27.

Division of Oncology, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8056, St. Louis, MO, 63110, USA,

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http://dx.doi.org/10.1007/s12032-014-0371-3DOI Listing
January 2015

De novo single exon deletion of AUTS2 in a patient with speech and language disorder: a review of disrupted AUTS2 and further evidence for its role in neurodevelopmental disorders.

Am J Med Genet A 2014 Apr 23;164A(4):958-65. Epub 2014 Jan 23.

Departments of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.

The autism susceptibility candidate 2 (AUTS2) gene is suggested to play a critical role in early brain development, and its association with intellectual disability (ID), autism spectrum disorders, and other neurodevelopmental disorders (NDDs) has recently gained more attention. Genomic rearrangements and copy number variations (CNVs) involving AUTS2 have been implicated in a range of NDDs with or without congenital malformations and dysmorphic features. Here we report a 62 kb de novo deletion encompassing exon 6 of AUTS2 detected by chromosomal microarray analysis (CMA) in a 4.5 year-old female patient with severe speech and language disorder, history of tonic-clonic movements, and pes planus with eversion of the feet. This is one of the smallest de novo intragenic deletions of AUTS2 described in patients with NDDs. We reviewed previously reported small pathogenic CNVs (<300 kb) in 19 cases, and correlated their specific locations within AUTS2 as well as presence of enhancers, regulatory elements, and CpG islands with the clinical findings of these cases and our patient. Our report provides additional insight into the clinical spectrum of AUTS2 disruptions.
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http://dx.doi.org/10.1002/ajmg.a.36393DOI Listing
April 2014

Familial microdeletion of 17q24.3 upstream of SOX9 is associated with isolated Pierre Robin sequence due to position effect.

Am J Med Genet A 2013 May 26;161A(5):1167-72. Epub 2013 Mar 26.

Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90024, USA.

Pierre Robin sequence (PRS) is a malformation pattern characterized by the core triad of retrognathia, glossoptosis, and cleft palate that causes difficulty in glossopharyngeal-laryngeal-vagal functions. The etiology of PRS remains largely unknown; previous reports have suggested that it is caused by intrauterine constriction or external conditions such as oligohydramnios, breech position, or abnormal uterine anatomy. Genetic causes include occurrence as a manifestation of many single gene conditions and chromosomal rearrangements. Positional effect on some loci or genes, including SOX9 has also been posited as a cause. Here, we report on an 18-month-old girl born with isolated PRS. Clinical chromosome microarray analysis (CMA) revealed a maternally inherited ~623 kb microdeletion that is -725 kb upstream of 5' SOX9 at chromosome locus 17q24.3. Her mother had cleft palate. This region, although devoid of any genes, is known to have a position effect on SOX9 due to elimination of highly conserved non-coding cis-regulatory elements. This report supports the evidence that deregulation of an intact SOX9 coding region is a cause of or associated with isolated PRS, and provides further evidence that CMA in the clinical setting is a powerful tool in detecting microdeletions in gene "desert" regions that have pathogenic position effect on specific genes.
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http://dx.doi.org/10.1002/ajmg.a.35847DOI Listing
May 2013

Atypical rearrangement involving 3'-IGH@ and a breakpoint at least 400 Kb upstream of an intact MYC in a CLL patient with an apparently balanced t(8;14)(q24.1;q32) and negative MYC expression.

Mol Cytogenet 2013 Feb 1;6(1). Epub 2013 Feb 1.

Clinical Molecular Cytogenetics Laboratory, Medicine, David Geffen UCLA School of Medicine, Los Angeles, CA, USA.

The t(8;14)(q24.1;q32), the cytogenetic hallmark of Burkitt's lymphoma, is also found, but rarely, in cases of chronic lymphocytic leukemia (CLL). Such translocation typically results in a MYC-IGH@ fusion subsequently deregulating and overexpressing MYC on der 14q32. In CLL, atypical rearrangements resulting in its gain or loss, within or outside of IGH@ or MYC locus, have been reported, but their clinical significance remains uncertain. Herein, we report a 67 year-old male with complex cytogenetic findings of apparently balanced t(8;14) and unreported complex rearrangements of IGH@ and MYC loci. His clinical, morphological and immunophenotypic features were consistent with the diagnosis of CLL.Interphase FISH studies revealed deletions of 11q22.3 and 13q14.3, and an extra copy of IGH@, indicative of rearrangement. Karyotype analysis showed an apparently balanced t(8;14)(q24.1;q32). Sequential GPG-metaphase FISH studies revealed abnormal signal patterns: rearrangement of IGH break apart probe with the 5'-IGH@ on derivative 8q24.1 and the 3'-IGH@ retained on der 14q; absence of MYC break apart-specific signal on der 8q; and, the presence of unsplit 5'-MYC-3' break apart probe signals on der 14q. The breakpoint on 8q24.1 was found to be at least 400 Kb upstream of 5' of MYC. In addition, FISH studies revealed two abnormal clones; one with 13q14.3 deletion, and the other, with concurrent 11q deletion and atypical rearrangements. Chromosome microarray analysis (CMA) detected a 7.1 Mb deletion on 11q22.3-q23.3 including ATM, a finding consistent with FISH results. While no significant copy number gain or loss observed on chromosomes 8, 12 and 13, a 455 Kb microdeletion of uncertain clinical significance was detected on 14q32.33. Immunohistochemistry showed co-expression of CD19, CD5, and CD23, positive ZAP-70 expression and absence of MYC expression. Overall findings reveal an apparently balanced t(8;14) and atypical complex rearrangements involving 3'-IGH@ and a breakpoint at least 400 Kb upstream of MYC, resulting in the relocation of the intact 5'-MYC-3' from der 8q, and apposition to 3'-IGH@ at der 14q. This case report provides unique and additional cytogenetic data that may be of clinical significance in such a rare finding in CLL. It also highlights the utility of conventional and sequential metaphase FISH in understanding complex chromosome anomalies and their association with other clinical findings in patients with CLL. To the best of our knowledge, this is the first CLL reported case with such an atypical rearrangement in a patient with a negative MYC expression.
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http://dx.doi.org/10.1186/1755-8166-6-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3599416PMC
February 2013

Solid tumor cytogenetics: current perspectives.

Clin Lab Med 2011 Dec 21;31(4):785-811, xi. Epub 2011 Oct 21.

Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, 2-226 Rehab Center, 1000 Veteran Avenue, Los Angeles, CA 90024, USA.

Conventional cytogenetics in conjunction with Fluorescence in Situ Hybridization (FISH) continues to remain an important and integral component in the diagnosis and management of solid tumors. The ability to effectively detect the vast majority of clinically relevant chromosomal aberrations with a rapid-to-acceptable turnaround time makes them the most cost-effective screening/detection tool currently available in modern pathology. In this review, we describe a representative set of solid tumors in which chromosomal analysis and/or FISH plays a significant role in the routine clinical management of solid tumors.
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http://dx.doi.org/10.1016/j.cll.2011.07.007DOI Listing
December 2011

Maize centromere mapping: a comparison of physical and genetic strategies.

J Hered 2008 Mar-Apr;99(2):85-93. Epub 2008 Jan 22.

Department of Agronomy and Plant Genetics, University of Minnesota, St Paul, MN 55108-6026, USA.

Centromere positions on 7 maize chromosomes were compared on the basis of data from 4 to 6 mapping techniques per chromosome. Centromere positions were first located relative to molecular markers by means of radiation hybrid lines and centric fission lines recovered from oat-maize chromosome addition lines. These centromere positions were then compared with new data from centric fission lines recovered from maize plants, half-tetrad mapping, and fluorescence in situ hybridizations and to data from earlier studies. Surprisingly, the choice of mapping technique was not the critical determining factor. Instead, on 4 chromosomes, results from all techniques were consistent with a single centromere position. On chromosomes 1, 3, and 6, centromere positions were not consistent even in studies using the same technique. The conflicting centromere map positions on chromosomes 1, 3, and 6 could be explained by pericentric inversions or alternative centromere positions on these chromosomes.
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http://dx.doi.org/10.1093/jhered/esm111DOI Listing
August 2008

A transgenomic cytogenetic sorghum (Sorghum propinquum) bacterial artificial chromosome fluorescence in situ hybridization map of maize (Zea mays L.) pachytene chromosome 9, evidence for regions of genome hyperexpansion.

Genetics 2007 Nov 18;177(3):1509-26. Epub 2007 Oct 18.

Department of Biological Science, Florida State University, Tallahassee, Florida 32306-4370.

A cytogenetic FISH map of maize pachytene-stage chromosome 9 was produced with 32 maize marker-selected sorghum BACs as probes. The genetically mapped markers used are distributed along the linkage maps at an average spacing of 5 cM. Each locus was mapped by means of multicolor direct FISH with a fluorescently labeled probe mix containing a whole-chromosome paint, a single sorghum BAC clone, and the centromeric sequence, CentC. A maize-chromosome-addition line of oat was used for bright unambiguous identification of the maize 9 fiber within pachytene chromosome spreads. The locations of the sorghum BAC-FISH signals were determined, and each new cytogenetic locus was assigned a centiMcClintock position on the short (9S) or long (9L) arm. Nearly all of the markers appeared in the same order on linkage and cytogenetic maps but at different relative positions on the two. The CentC FISH signal was localized between cdo17 (at 9L.03) and tda66 (at 9S.03). Several regions of genome hyperexpansion on maize chromosome 9 were found by comparative analysis of relative marker spacing in maize and sorghum. This transgenomic cytogenetic FISH map creates anchors between various maps of maize and sorghum and creates additional tools and information for understanding the structure and evolution of the maize genome.
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http://dx.doi.org/10.1534/genetics.107.080846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2147981PMC
November 2007