Publications by authors named "Sulagna Saitta"

38 Publications

Custom Pediatric Oncology Next-Generation Sequencing Panel Identifies Somatic Mosaicism in Archival Tissue and Enhances Targeted Clinical Care.

Pediatr Neurol 2021 01 2;114:55-59. Epub 2020 Oct 2.

Foundation Medicine, Cambridge, Massachusetts.

Background: Disorders in the PIK3CA-related overgrowth spectrum because of somatic mosaicism are associated with segmental overgrowth of the body in conjunction with vascular, skeletal, and brain malformations such as hemimegalencephaly. A pathogenic variant may only be detectable in affected tissue and not in peripheral blood or saliva samples; therefore archival tissue may be the only relevant available specimen for testing. Although this is a common approach for cancer testing, it is not typically used for constitutional genetic disorders.

Methods: PIK3CA mosaicism was assessed with a custom pediatric oncology next-generation sequencing panel (OncoKids) designed to capture somatic mutations in pediatric malignancies. The panel covers a wide range of targets including PIK3CA and AKT1 hotspots. We used OncoKids on archival formalin-fixed, paraffin-embedded or frozen samples from seven patients with facial hemihypertrophy and lipomas, hemimegalencephaly, or hemihypertrophy with a lymphovascular malformation. The age of the archival tissue examined by next-generation sequencing ranged from two to 13 years (median 5 years). Every patient had clinical manifestations within the PIK3CA-related overgrowth spectrum and had a sample of an affected tissue available for testing from a prior surgical intervention.

Results: PIK3CA mosaicism was detected in all seven patients and the mutant allele fraction was lower in the lymphovascular malformation tissues (8% to 11%) than in brain (20% to 32%) and lipomatous (16% to 23%) tissues.

Conclusions: Our study highlights the clinical utility of using a robust, oncology-focused next-generation sequencing assay to identify PIK3CA mosaicism in noncancer cases. It is feasible to use archival samples that are more than a decade old to obtain a molecular diagnosis, which can then be used to improve health care management.
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http://dx.doi.org/10.1016/j.pediatrneurol.2020.09.015DOI Listing
January 2021

Tracking the motion of the K 1.2 voltage sensor reveals the molecular perturbations caused by a de novo mutation in a case of epilepsy.

J Physiol 2020 11 21;598(22):5245-5269. Epub 2020 Sep 21.

Division of Molecular Medicine, Department of Anesthesiology & Perioperative Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.

Key Points: K 1.2 channels, encoded by the KCNA2 gene, regulate neuronal excitability by conducting K upon depolarization. A new KCNA2 missense variant was discovered in a patient with epilepsy, causing amino acid substitution F302L at helix S4, in the K 1.2 voltage-sensing domain. Immunocytochemistry and flow cytometry showed that F302L does not impair KCNA2 subunit surface trafficking. Molecular dynamics simulations indicated that F302L alters the exposure of S4 residues to membrane lipids. Voltage clamp fluorometry revealed that the voltage-sensing domain of K 1.2-F302L channels is more sensitive to depolarization. Accordingly, K 1.2-F302L channels opened faster and at more negative potentials; however, they also exhibited enhanced inactivation: that is, F302L causes both gain- and loss-of-function effects. Coexpression of KCNA2-WT and -F302L did not fully rescue these effects. The proband's symptoms are more characteristic of patients with loss of KCNA2 function. Enhanced K 1.2 inactivation could lead to increased synaptic release in excitatory neurons, steering neuronal circuits towards epilepsy.

Abstract: An exome-based diagnostic panel in an infant with epilepsy revealed a previously unreported de novo missense variant in KCNA2, which encodes voltage-gated K channel K 1.2. This variant causes substitution F302L, in helix S4 of the K 1.2 voltage-sensing domain (VSD). F302L does not affect KCNA2 subunit membrane trafficking. However, it does alter channel functional properties, accelerating channel opening at more hyperpolarized membrane potentials, indicating gain of function. F302L also caused loss of K 1.2 function via accelerated inactivation onset, decelerated recovery and shifted inactivation voltage dependence to more negative potentials. These effects, which are not fully rescued by coexpression of wild-type and mutant KCNA2 subunits, probably result from the enhancement of VSD function, as demonstrated by optically tracking VSD depolarization-evoked conformational rearrangements. In turn, molecular dynamics simulations suggest altered VSD exposure to membrane lipids. Compared to other encephalopathy patients with KCNA2 mutations, the proband exhibits mild neurological impairment, more characteristic of patients with KCNA2 loss of function. Based on this information, we propose a mechanism of epileptogenesis based on enhanced K 1.2 inactivation leading to increased synaptic release preferentially in excitatory neurons, and hence the perturbation of the excitatory/inhibitory balance of neuronal circuits.
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http://dx.doi.org/10.1113/JP280438DOI Listing
November 2020

Embryonal rhabdomyosarcoma in a patient with a germline CBL pathogenic variant.

Cancer Genet 2019 02 30;231-232:62-66. Epub 2018 Dec 30.

Department of Pathology & Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA; Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Germline pathogenic variants in CBL are associated with an autosomal dominant RASopathy and an increased risk for malignancies, particularly juvenile myelomonocytic leukemia. Herein, we describe a patient with clinical features of a Noonan-spectrum disorder who developed embryonal rhabdomyosarcoma of the bladder at age two years. Tumor analysis using the OncoKids cancer panel revealed a CBL pathogenic variant: NM_005188.3:c.1100A>C (p.Gln367Pro). Sanger sequencing of peripheral blood DNA confirmed a de novo heterozygous germline variant. This is the first report of embryonal rhabdomyosarcoma in association with a germline CBL pathogenic variant, further broadening the CBL cancer predisposition spectrum.
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http://dx.doi.org/10.1016/j.cancergen.2018.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528629PMC
February 2019

A semiautomated whole-exome sequencing workflow leads to increased diagnostic yield and identification of novel candidate variants.

Cold Spring Harb Mol Case Stud 2019 04 1;5(2). Epub 2019 Apr 1.

Center for Personalized Medicine, Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California 90027, USA.

Advancing the clinical utility of whole-exome sequencing (WES) for patients with suspected genetic disorders is largely driven by bioinformatics approaches that streamline data processing and analysis. Herein, we describe our experience with implementing a semiautomated and phenotype-driven WES diagnostic workflow, incorporating both the DRAGEN pipeline and the Exomiser variant prioritization tool, at an academic children's hospital with an ethnically diverse pediatric patient population. We achieved a 41% molecular diagnostic rate for 66 duo-, quad-, or trio-WES cases, and 28% for 40 singleton-WES cases. Preliminary results were returned to ordering physicians within 1 wk for 12 of 38 (32%) probands with positive findings, which were instrumental in guiding the appropriate clinical management for a variety of patients, especially in critical care settings. The semiautomated and streamlined WES workflow also enabled us to identify novel variants in candidate disease genes in patients with developmental delay and autism and immune disorders and cancer, including , , , , , and Together, we demonstrated the implementation of a streamlined WES workflow that was successfully applied for both clinical and research purposes.
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http://dx.doi.org/10.1101/mcs.a003756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549575PMC
April 2019

Immune and Genetic Features of the Chromosome 22q11.2 Deletion (DiGeorge Syndrome).

Curr Allergy Asthma Rep 2018 10 30;18(12):75. Epub 2018 Oct 30.

Department of Pathology, Division of Genomic Medicine, Children's Hospital Los Angeles, USC Keck School of Medicine, 4650 Sunset Blvd, Los Angeles, CA, 90027, USA.

Purpose Of Review: This review provides an update on the progress in identifying the range of immunological dysfunction seen in DiGeorge syndrome and on more recent diagnostic and treatment approaches.

Recent Findings: Clinically, the associated thymic hypoplasia/aplasia is well known and can have profound effects on T cell function. Further, the humoral arm of the immune system can be affected, with hypogammaglobulinemia and poor vaccine-specific antibody response. Additionally, genetic testing utilizing chromosomal microarray demonstrates a small but significant number of 22q11 deletions that are not detectable by standard FISH testing. The recent addition of a TREC assay to newborn screening can identify a subset of infants whose severe immune defects may result from 22q11 deletion. This initial presentation now also places the immunologist in the role of "first responder" with regard to diagnosis and management of these patients. DiGeorge syndrome reflects a clinical phenotype now recognized by its underlying genetic diagnosis, chromosome 22q11.2 deletion syndrome, which is associated with multisystem involvement and variable immune defects among patients. Updated genetic and molecular techniques now allow for earlier identification of immune defects and confirmatory diagnoses, in this disorder with life-long clinical issues.
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http://dx.doi.org/10.1007/s11882-018-0823-5DOI Listing
October 2018

Nonreentrant atrial tachycardia occurs independently of hypertrophic cardiomyopathy in RASopathy patients.

Am J Med Genet A 2018 08 28;176(8):1711-1722. Epub 2018 Jul 28.

Genetics Unit, MassGeneral Hospital for Children, Boston, Massachusetts.

Multifocal atrial tachycardia (MAT) has a well-known association with Costello syndrome, but is rarely described with related RAS/MAPK pathway disorders (RASopathies). We report 11 patients with RASopathies (Costello, Noonan, and Noonan syndrome with multiple lentigines [formerly LEOPARD syndrome]) and nonreentrant atrial tachycardias (MAT and ectopic atrial tachycardia) demonstrating overlap in cardiac arrhythmia phenotype. Similar overlap is seen in RASopathies with respect to skeletal, musculoskeletal and cutaneous abnormalities, dysmorphic facial features, and neurodevelopmental deficits. Nonreentrant atrial tachycardias may cause cardiac compromise if sinus rhythm is not restored expeditiously. Typical first-line supraventricular tachycardia anti-arrhythmics (propranolol and digoxin) were generally not effective in restoring or maintaining sinus rhythm in this cohort, while flecainide or amiodarone alone or in concert with propranolol were effective anti-arrhythmic agents for acute and chronic use. Atrial tachycardia resolved in all patients. However, a 4-month-old boy from the cohort was found asystolic (with concurrent cellulitis) and a second patient underwent cardiac transplant for heart failure complicated by recalcitrant atrial arrhythmia. While propranolol alone frequently failed to convert or maintain sinus rhythm, fleccainide or amiodarone, occasionally in combination with propranolol, was effective for RASopathy patient treatment for nonreentrant atrial arrhythmia. Our analysis shows that RASopathy patients may have nonreentrant atrial tachycardia with and without associated cardiac hypertrophy. While nonreentrant arrhythmia has been traditionally associated with Costello syndrome, this work provides an expanded view of RASopathy cardiac arrhythmia phenotype as we demonstrate mutant proteins throughout this signaling pathway can also give rise to ectopic and/or MAT.
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http://dx.doi.org/10.1002/ajmg.a.38854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107379PMC
August 2018

Interstitial Chromosome 3p13p14 Deletions: An Update and Review.

Mol Syndromol 2018 May 7;9(3):122-133. Epub 2018 Apr 7.

Center for Personalized Medicine, Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles.

Deletions of proximal chromosome 3p13p14 are infrequent chromosomal alterations. Variable sizes and breakpoints have been reported in patients with a wide range of phenotypes that are evolving as additional cases are reported. The routine use of high-density chromosomal microarrays (CMA) has allowed the identification of many more cases of this disorder and clinical phenotyping shows evidence for an emerging profile among patients with overlapping deletions of 3p13p14. Here, we review the currently reported cases, their phenotypes and where available, the genomic intervals delineated by CMA. Surprisingly, we found that a significant number of proximal chromosome 3p deletions involve structural rearrangements, especially insertions, that have been identified in balanced parental chromosome complements. This region is historically known as a common human chromosomal fragile site, although an underlying genomic mechanism related to its architecture has not been identified. We conclude that identification of an interstitial 3p deletion in a proband by CMA should prompt consideration of further structural chromosomal evaluation using more traditional cytogenetic techniques. While the variability in breakpoints does not suggest a unifying underlying mechanism for these alterations, identification of the haploinsufficient genes in each patient's deletion interval and their developmental roles can guide genotype-phenotype correlations and impact clinical management.
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http://dx.doi.org/10.1159/000488168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006617PMC
May 2018

Further delineation of an entity caused by CREBBP and EP300 mutations but not resembling Rubinstein-Taybi syndrome.

Am J Med Genet A 2018 04 20;176(4):862-876. Epub 2018 Feb 20.

Department of Pediatrics, Academic Medical Center, Amsterdam, The Netherlands.

In 2016, we described that missense variants in parts of exons 30 and 31 of CREBBP can cause a phenotype that differs from Rubinstein-Taybi syndrome (RSTS). Here we report on another 11 patients with variants in this region of CREBBP (between bp 5,128 and 5,614) and two with variants in the homologous region of EP300. None of the patients show characteristics typical for RSTS. The variants were detected by exome sequencing using a panel for intellectual disability in all but one individual, in whom Sanger sequencing was performed upon clinical recognition of the entity. The main characteristics of the patients are developmental delay (90%), autistic behavior (65%), short stature (42%), and microcephaly (43%). Medical problems include feeding problems (75%), vision (50%), and hearing (54%) impairments, recurrent upper airway infections (42%), and epilepsy (21%). Major malformations are less common except for cryptorchidism (46% of males), and cerebral anomalies (70%). Individuals with variants between bp 5,595 and 5,614 of CREBBP show a specific phenotype (ptosis, telecanthi, short and upslanted palpebral fissures, depressed nasal ridge, short nose, anteverted nares, short columella, and long philtrum). 3D face shape demonstrated resemblance to individuals with a duplication of 16p13.3 (the region that includes CREBBP), possibly indicating a gain of function. The other affected individuals show a less specific phenotype. We conclude that there is now more firm evidence that variants in these specific regions of CREBBP and EP300 result in a phenotype that differs from RSTS, and that this phenotype may be heterogeneous.
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http://dx.doi.org/10.1002/ajmg.a.38626DOI Listing
April 2018

Inherited germline ATRX mutation in two brothers with ATR-X syndrome and osteosarcoma.

Am J Med Genet A 2017 May 28;173(5):1390-1395. Epub 2017 Mar 28.

Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, California.

We report a family in which two brothers had an undiagnosed genetic disorder comprised of dysmorphic features, microcephaly, severe intellectual disability (non-verbal), mild anemia, and cryptorchidism. Both developed osteosarcoma. Trio exome sequencing (using blood samples from the younger brother and both parents) was performed and a nonsense NM_000489.4:c.7156C>T (p.Arg2386*) mutation in the ATRX gene was identified in the proband (hemizygous) and in the mother's peripheral blood DNA (heterozygous). The mother is healthy, does not exhibit any clinical manifestations of ATR-X syndrome and there was no family history of cancer. The same hemizygous pathogenic variant was confirmed in the affected older brother's skin tissue by subsequent Sanger sequencing. Chromosomal microarray studies of both brothers' osteosarcomas revealed complex copy number alterations consistent with the clinical diagnosis of osteosarcoma. Recently, somatic mutations in the ATRX gene have been observed as recurrent alterations in both osteosarcoma and brain tumors. However, it is unclear if there is any association between osteosarcoma and germline ATRX mutations, specifically in patients with constitutional ATR-X syndrome. This is the first report of osteosarcoma diagnosed in two males with ATR-X syndrome, suggesting a potential increased risk for cancer in patients with this disorder.
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http://dx.doi.org/10.1002/ajmg.a.38184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521841PMC
May 2017

-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution.

JCI Insight 2016 06;1(9)

Division of Genetics, Department of Pediatrics, and.

Mosaicism is increasingly recognized as a cause of developmental disorders with the advent of next-generation sequencing (NGS). Mosaic mutations of have been associated with the widest spectrum of phenotypes associated with overgrowth and vascular malformations. We performed targeted NGS using 2 independent deep-coverage methods that utilize molecular inversion probes and amplicon sequencing in a cohort of 241 samples from 181 individuals with brain and/or body overgrowth. We identified mutations in 60 individuals. Several other individuals ( = 12) were identified separately to have mutations in by clinical targeted-panel testing ( = 6), whole-exome sequencing ( = 5), or Sanger sequencing ( = 1). Based on the clinical and molecular features, this cohort segregated into three distinct groups: (a) severe focal overgrowth due to low-level but highly activating (hotspot) mutations, (b) predominantly brain overgrowth and less severe somatic overgrowth due to less-activating mutations, and (c) intermediate phenotypes (capillary malformations with overgrowth) with intermediately activating mutations. Sixteen of 29 mutations were novel. We also identified constitutional mutations in 10 patients. Our molecular data, combined with review of the literature, show that -related overgrowth disorders comprise a discontinuous spectrum of disorders that correlate with the severity and distribution of mutations.
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http://dx.doi.org/10.1172/jci.insight.87623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5019182PMC
June 2016

Mutations in TKT Are the Cause of a Syndrome Including Short Stature, Developmental Delay, and Congenital Heart Defects.

Am J Hum Genet 2016 06;98(6):1235-1242

Department of Pediatrics, Columbia University, New York, NY 10032, USA; Department of Medicine, Columbia University, New York, NY 10032, USA. Electronic address:

Whole-exome sequencing (WES) is increasingly being utilized to diagnose individuals with undiagnosed disorders. Developmental delay and short stature are common clinical indications for WES. We performed WES in three families, using proband-parent trios and two additional affected siblings. We identified a syndrome due to an autosomal-recessively inherited deficiency of transketolase, encoded by TKT, on chromosome 3p21. Our series includes three families with a total of five affected individuals, ranging in age from 4 to 25 years. Two families of Ashkenazi Jewish ancestry were homozygous for an 18 base pair in-frame insertion in TKT. The third family was compound heterozygous for nonsense and missense variants in TKT. All affected individuals had short stature and were developmentally delayed. Congenital heart defects were noted in four of the five affected individuals, and there was a history of chronic diarrhea and cataracts in the older individuals with the homozygous 18 base pair insertion. Enzymatic testing confirmed significantly reduced transketolase activity. Elevated urinary excretion of erythritol, arabitol, ribitol, and pent(ul)ose-5-phosphates was detected, as well as elevated amounts of erythritol, arabitol, and ribitol in the plasma of affected individuals. Transketolase deficiency reduces NADPH synthesis and nucleic acid synthesis and cell division and could explain the problems with growth. NADPH is also critical for maintaining cerebral glutathione, which might contribute to the neurodevelopmental delays. Transketolase deficiency is one of a growing list of inborn errors of metabolism in the non-oxidative part of the pentose phosphate pathway.
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http://dx.doi.org/10.1016/j.ajhg.2016.03.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908149PMC
June 2016

Interstitial Chromosome 3p14.1 Deletion due to a Maternal Insertion: Phenotype and Association with Balanced Parental Rearrangement.

Mol Syndromol 2016 Apr 16;7(1):43-8. Epub 2016 Mar 16.

Division of Medical Genetics, Department of Pediatrics, Cedars-Sinai Medical Center, San Juan Capistrano, Calif., USA; Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, Calif., USA.

Interstitial deletions of 3p14p12 are rare chromosome abnormalities. We present a patient with multiple congenital anomalies and a 15.4-Mb interstitial loss of chromosome 3p14p12 detected by chromosomal microarray (CMA). Our patient shared many phenotypic features with other reported cases involving the same region including prominent forehead, short palpebral fissures, hand and foot anomalies, genital abnormalities, and bilateral hearing loss. Given the clinical similarity of these cases with significant overlap of the deleted regions, it is likely that the phenotype is related to the deletion of specific genes within the region. Further molecular cytogenetic investigation revealed that our patient's rearrangement was derived from a cryptic insertion of a segment of chromosome 3p into chromosome 18q in the mother, which was balanced and therefore not visible on the mother's CMA. To our knowledge, this finding has not been previously reported. This case illustrates the importance of using molecular cytogenetics for structural analysis and parental studies. CMA is commonly the first-line study in patients with multiple congenital anomalies; however, it is not the appropriate modality to define a structural rearrangement that may be the cause of a deletion. The use of adjunct studies to define the mechanism of an identified copy number aberration has direct clinical application: to identify the underlying cause of the chromosomal abnormality and to define the recurrence risk. Additionally, this case adds to the current body of work regarding a recurrent phenotype that can be attributed to interstitial chromosome 3p deletions, which may help define the phenotypic implications of deletions in this region and support early clinical management.
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http://dx.doi.org/10.1159/000444603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4862392PMC
April 2016

Intragenic KANSL1 mutations and chromosome 17q21.31 deletions: broadening the clinical spectrum and genotype-phenotype correlations in a large cohort of patients.

J Med Genet 2015 Dec 30;52(12):804-14. Epub 2015 Sep 30.

Division of Clinical Genetics, Children's Hospital of Philadelphia, Philadelphia, USA.

Background: The 17q21.31 deletion syndrome phenotype can be caused by either chromosome deletions or point mutations in the KANSL1 gene. To date, about 60 subjects with chromosome deletion and 4 subjects with point mutation in KANSL1 have been reported. Prevalence of chromosome deletions compared with point mutations, genotype-phenotype correlations and phenotypic variability have yet to be fully clarified.

Methods: We report genotype-phenotype correlations in 27 novel subjects with 17q21.31 deletion and in 5 subjects with KANSL1 point mutation, 3 of whom were not previously reported.

Results: The prevalence of chromosome deletion and KANSL1 mutation was 83% and 17%, respectively. All patients had similar clinical features, with the exception of macrocephaly, which was detected in 24% of patients with the deletion and 60% of those with the point mutation, and congenital heart disease, which was limited to 35% of patients with the deletion. A remarkable phenotypic variability was observed in both categories, mainly with respect to the severity of ID. Cognitive function was within normal parameters in one patient in each group. Craniosynostosis, subependymal heterotopia and optic nerve hypoplasia represent new component manifestations.

Conclusions: In KANSL1 haploinsufficiency syndrome, chromosome deletions are greatly prevalent compared with KANSL1 mutations. The latter are sufficient in causing the full clinical phenotype. The degree of intellectual disability (ID) appears to be milder than expected in a considerable number of subjects with either chromosome deletion or KANSL1 mutation. Striking clinical criteria for enrolling patients into KANSL1 analysis include speech delay, distinctive facial dysmorphism, macrocephaly and friendly behaviour.
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http://dx.doi.org/10.1136/jmedgenet-2015-103184DOI Listing
December 2015

PIAS4 is associated with macro/microcephaly in the novel interstitial 19p13.3 microdeletion/microduplication syndrome.

Eur J Hum Genet 2015 Dec 8;23(12):1615-26. Epub 2015 Apr 8.

Section of Functional and Structural Genomics Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain.

Array comparative genomic hybridization (aCGH) is a powerful genetic tool that has enabled the identification of novel imbalances in individuals with intellectual disability (ID), autistic disorders and congenital malformations. Here we report a 'genotype first' approach using aCGH on 13 unrelated patients with 19p13.3 submicroscopic rearrangement (11 deletions and 2 duplications) and review cases in the literature and in public databases. Shared phenotypic features suggest that these patients represent an interstitial microdeletion/microduplication syndrome at 19p13.3. Common features consist of abnormal head circumference in most patients (macrocephaly with the deletions and microcephaly with the duplications), ID with developmental delay (DD), hypotonia, speech delay and common dysmorphic features. The phenotype is associated with at least a ~0.113 Mb critical region harboring three strong candidate genes probably associated with DD, ID, speech delay and other dysmorphic features: MAP2K2, ZBTB7A and PIAS4, an E3 ubiquitin ligase involved in the ubiquitin signaling pathways, which we hypothesize for the first time to be associated with head size in humans.
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http://dx.doi.org/10.1038/ejhg.2015.51DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4795197PMC
December 2015

TUBB4A de novo mutations cause isolated hypomyelination.

Neurology 2014 Sep 1;83(10):898-902. Epub 2014 Aug 1.

Authors' affiliations are listed at the end of the article.

Objective: We present a series of unrelated patients with isolated hypomyelination, with or without mild cerebellar atrophy, and de novo TUBB4A mutations.

Methods: Patients in 2 large institutional review board-approved leukodystrophy bioregistries at Children's National Medical Center and Montreal Children's Hospital with similar MRI features had whole-exome sequencing performed. MRIs and clinical information were reviewed.

Results: Five patients who presented with hypomyelination without the classic basal ganglia abnormalities were found to have novel TUBB4A mutations through whole-exome sequencing. Clinical and imaging characteristics were reviewed suggesting a spectrum of clinical manifestations.

Conclusion: Hypomyelinating leukodystrophies remain a diagnostic challenge with a large percentage of unresolved cases. This finding expands the phenotype of TUBB4A-related hypomyelinating conditions beyond hypomyelination with atrophy of the basal ganglia and cerebellum. TUBB4A mutation screening should be considered in cases of isolated hypomyelination or hypomyelination with nonspecific cerebellar atrophy.
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http://dx.doi.org/10.1212/WNL.0000000000000754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4153852PMC
September 2014

Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance.

Hum Mol Genet 2014 Jun 8;23(11):2888-900. Epub 2014 Jan 8.

Sektion für Funktionelle Genetik am Institut für Humangenetik, Universität zu Lübeck, Lübeck 23538, Germany.

Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for ∼5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS.
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http://dx.doi.org/10.1093/hmg/ddu002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4014191PMC
June 2014

Clinical features of three girls with mosaic genome-wide paternal uniparental isodisomy.

Am J Med Genet A 2013 Aug 26;161A(8):1929-39. Epub 2013 Jun 26.

The Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

Here we describe three subjects with mosaic genome-wide paternal uniparental isodisomy (GWpUPD) each of whom presented initially with overgrowth, hemihyperplasia (HH), and hyperinsulinism (HI). Due to the severity of findings and the presence of additional features, SNP array testing was performed, which demonstrated mosaic GWpUPD. Comparing these individuals to 10 other live-born subjects reported in the literature, the predominant phenotype is that of pUPD11 and notable for a very high incidence of tumor development. Our subjects developed non-metastatic tumors of the adrenal gland, kidney, and/or liver. All three subjects had pancreatic hyperplasia resulting in HI. Notably, our subjects to date display minimal features of other diseases associated with paternal UPD loci. Both children who survived the neonatal period have displayed near-normal cognitive development, likely due to a favorable tissue distribution of the mosaicism. To understand the range of UPD mosaicism levels, we studied multiple tissues using SNP array analysis and detected levels of 5-95%, roughly correlating with the extent of tissue involvement. Given the rapidity of tumor growth and the difficulty distinguishing malignant and benign tumors in these GWpUPD subjects, we have utilized increased frequency of ultrasound (US) and alpha-fetoprotein (AFP) screening in the first years of life. Because of a later age of onset of additional tumors, continued tumor surveillance into adolescence may need to be considered in these rare patients.
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http://dx.doi.org/10.1002/ajmg.a.36045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4082120PMC
August 2013

Duplication 12p and Pallister-Killian syndrome: a case report and review of the literature toward defining a Pallister-Killian syndrome minimal critical region.

Am J Med Genet A 2012 Dec 20;158A(12):3033-45. Epub 2012 Nov 20.

Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.

Pallister-Killian syndrome (PKS) is a multisystem sporadic genetic condition characterized by facial anomalies, variable developmental delay and intellectual impairment, hypotonia, hearing loss, seizures, pigmentary skin differences, temporal alopecia, diaphragmatic hernia, congenital heart defects, and other systemic abnormalities. PKS is typically caused by the presence of a supernumerary isochromosome composed of the short arms of chromosome 12 resulting in tetrasomy 12p, which is often present in a tissue limited mosaic state. The PKS phenotype has also often been observed in individuals with complete or partial duplications of 12p (trisomy 12p rather than tetrasomy 12p) as the result of an interstitial duplication or unbalanced translocation. We have identified a proposita with PKS who has two small de novo interstitial duplications of 12p which, along with a review of previously reported cases, has allowed us to define a minimum critical region for PKS.
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http://dx.doi.org/10.1002/ajmg.a.35500DOI Listing
December 2012

The core FOXG1 syndrome phenotype consists of postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and corpus callosum hypogenesis.

J Med Genet 2011 Jun 25;48(6):396-406. Epub 2011 Mar 25.

Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Campus Forschung, Martinistraße 52, 20246 Hamburg, Germany.

Background: Submicroscopic deletions in 14q12 spanning FOXG1 or intragenic mutations have been reported in patients with a developmental disorder described as a congenital variant of Rett syndrome. This study aimed to further characterise and delineate the phenotype of FOXG1 mutation positive patients.

Method: The study mapped the breakpoints of a 2;14 translocation by fluorescence in situ hybridisation and analysed three chromosome rearrangements in 14q12 by cytogenetic analysis and/or array comparative genomic hybridisation. The FOXG1 gene was sequenced in 210 patients, including 129 patients with unexplained developmental disorders and 81 MECP2 mutation negative individuals.

Results: One known mutation, seen in two patients, and nine novel mutations of FOXG1 including two deletions, two chromosome rearrangements disrupting or displacing putative cis-regulatory elements from FOXG1, and seven sequence changes, are reported. Analysis of 11 patients in this study, and a further 15 patients reported in the literature, demonstrates a complex constellation of features including mild postnatal growth deficiency, severe postnatal microcephaly, severe mental retardation with absent language development, deficient social reciprocity resembling autism, combined stereotypies and frank dyskinesias, epilepsy, poor sleep patterns, irritability in infancy, unexplained episodes of crying, recurrent aspiration, and gastro-oesophageal reflux. Brain imaging studies reveal simplified gyral pattern and reduced white matter volume in the frontal lobes, corpus callosum hypogenesis, and variable mild frontal pachgyria.

Conclusions: These findings have significantly expanded the number of FOXG1 mutations and identified two affecting possible cis-regulatory elements. While the phenotype of the patients overlaps both classic and congenital Rett syndrome, extensive clinical evaluation demonstrates a distinctive and clinically recognisable phenotype which the authors suggest designating as the FOXG1 syndrome.
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http://dx.doi.org/10.1136/jmg.2010.087528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522617PMC
June 2011

High-Resolution genomic arrays identify CNVs that phenocopy the chromosome 22q11.2 deletion syndrome.

Hum Mutat 2011 Jan;32(1):91-7

Children's Hospital of Philadelphia, Pennsylvania, USA.

The 22q11 Deletion Syndrome includes the overlapping phenotypes of DiGeorge/Velocardiofacial Syndromes, characterized by conotruncal heart defects, cleft palate, thymus, and parathyroid gland dysplasia. The majority (90%) of patients harbor detectable chr22q11.2 deletions, but a genetic etiology for the remainder of patients without a deletion can remain undefined despite major birth defects. We analyzed DNA from eight patients with normal 22q11 FISH studies by high-density single nucleotide polymorphism (SNP) arrays and identified potentially pathogenic copy number variants (CNVs) in four of eight patients. Two patients showed large CNVs in regions of known genomic disorders: one a deletion of distal chr22q11.2 and the other a duplication of chr5q35. A 3-Mb deletion of chr19p13.3 that includes a gene associated with conotruncal heart defects was found in a third patient. Two potentially pathogenic CNVs were found in a fourth patient: a large heterozygous deletion of chr6p24 and a smaller duplication of chr9p24. Our findings support a recent consensus statement advocating chromosomal microarray analysis as a first-line diagnostic approach for patients with multiple congenital anomalies. In patients with phenotypes suggestive of the 22q11.2 syndrome spectrum and normal FISH, microarray analysis can uncover the molecular basis of other genomic disorders whose features overlap those of 22q11.2 deletions.
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http://dx.doi.org/10.1002/humu.21395DOI Listing
January 2011

Recurrent interstitial 1p36 deletions: Evidence for germline mosaicism and complex rearrangement breakpoints.

Am J Med Genet A 2010 Dec;152A(12):3074-83

Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.

Deletions of chromosome 1p36 are one of the most frequently encountered subtelomeric alterations. Clinical features of monosomy 1p36 include neurocognitive impairment, hearing loss, seizures, cardiac defects, and characteristic facial features. The majority of cases have occurred sporadically, implying that genomic instability plays a role in the prevalence of the syndrome. Here, we report two siblings with mild phenotypic features of the deletion syndrome, including developmental delay, hearing loss, and left ventricular non-compaction (LVNC). Microarray analysis using bacterial artificial chromosome and oligonucleotide microarrays indicated the deletions were identical, suggesting germline mosaicism. Parental phenotypes were normal, and analysis by fluorescence in situ hybridization (FISH) did not show mosaicism. These small interstitial deletions were not detectable by conventional subtelomeric FISH analysis. To investigate the mechanism of deletion further, the breakpoints were cloned and sequenced, demonstrating the presence of a complex rearrangement. Sequence analysis of genes in the deletion interval did not reveal any mutations on the intact homologue that may have contributed to the LVNC seen in both children. This is the first report of apparent germline mosaicism for this disorder. Thus, our findings have important implications for diagnostic approaches and for recurrence risk counseling in families with a child with monosomy 1p36. In addition, our results further refine the minimal critical region for LVNC and hearing loss.
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http://dx.doi.org/10.1002/ajmg.a.33733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058890PMC
December 2010

Agenesis of the corpus callosum and congenital lymphedema: A novel recognizable syndrome?

Am J Med Genet A 2010 Jul;152A(7):1621-6

Medical Genetics Research Group and Regional Genetics Service, St Mary's Hospital, Manchester, UK.

We present double first cousins, a girl and a boy, with the uncommon association of agenesis of the corpus callosum and congenital lymphedema. Other features shared by both include oligohydramnios, similar facial dysmorphism, sacral dimple, developmental delay, and sociable personality. While some of these findings overlap with FG syndrome and Hennekam syndrome, the findings in our patients are sufficiently different to exclude these diagnoses. We propose that this is a new syndrome with presumed autosomal recessive inheritance.
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http://dx.doi.org/10.1002/ajmg.a.33200DOI Listing
July 2010

Impact of genotype-first diagnosis: the detection of microdeletion and microduplication syndromes with cancer predisposition by aCGH.

Genet Med 2009 May;11(5):314-22

Signature Genomic Laboratories, LLC, Spokane, Washington, USA.

Background: The use of microarray-based comparative genomic hybridization has allowed the genetic diagnosis of some conditions before their full clinical presentation. This "genotype-first" diagnosis has the most clinical implications for genomic alterations that confer an elevated risk of cancer. In these cases, diagnosis before the manifestation of the patient's full phenotype dramatically impacts genetic counseling, clinical management, and eventual prognosis and survivability.

Methods: Using microarray-based comparative genomic hybridization, we tested 18,437 individuals with indications such as developmental disabilities and congenital anomalies.

Results: We identified 34 (0.18%) individuals with DNA copy number gains or losses that encompassed gene regions associated with recognized genetic conditions with an increased risk for cancer. Three of the 34 individuals (8.8%) had a previously abnormal cytogenetic study which microarray-based comparative genomic hybridization confirmed and/or further characterized. Seven of the 34 individuals (20.6%) either had the correct disease specified in the clinical indication for study or had clinical features highly indicative of that syndrome. The remaining 24 patients (70.6%) had indications for study that were not specific to the diagnosed syndrome, such as "developmental delay" or "dysmorphic features."

Conclusions: The ability of microarray-based comparative genomic hybridization to rapidly and objectively interrogate the genome for chromosomal imbalances has led to the opportunity to optimize medical management and outcome. This has an even more profound impact and clinical utility in conditions associated with cancer predisposition syndromes.
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http://dx.doi.org/10.1097/GIM.0b013e3181a028a5DOI Listing
May 2009

Identification of familial and de novo microduplications of 22q11.21-q11.23 distal to the 22q11.21 microdeletion syndrome region.

Hum Mol Genet 2009 Apr 3;18(8):1377-83. Epub 2009 Feb 3.

Signature Genomic Laboratories, LLC, Spokane, WA 99207, USA.

Deletions of the 22q11.2 region distal to the 22q11.21 microdeletion syndrome region have recently been described in individuals with mental retardation and congenital anomalies. Because these deletions are mediated by low-copy repeats (LCRs), located distal to the 22q11.21 DiGeorge/velocardiofacial microdeletion region, duplications are predicted to occur with a frequency equal to the deletion. However, few microduplications of this region have been reported. We report the identification of 18 individuals with microduplications of 22q11.21-q11.23. The duplication boundaries for all individuals are within LCRs distal to the DiGeorge/velocardiofacial microdeletion region. Clinical records for nine subjects reveal shared characteristics, but also several examples of contradicting clinical features (e.g. macrocephaly versus microcephaly and upslanting versus downslanting palpebral fissures). Of 12 cases for whom parental DNA samples were available for testing, one is de novo and 11 inherited the microduplication from a parent, three of whom reportedly have learning problems or developmental delay. The variable phenotypes and preponderance of familial cases obfuscate the clinical relevance of the molecular data and emphasize the need for careful parental assessments and clinical correlations.
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http://dx.doi.org/10.1093/hmg/ddp042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2664143PMC
April 2009

MAP'ing CNS development and cognition: an ERKsome process.

Neuron 2009 Jan;61(2):160-7

Department of Neurosciences, Case Western Reserve University, Cleveland, OH 44106, USA.

The ERK MAP kinase signaling cascade plays critical roles in brain development, learning, memory, and cognition. It has recently been appreciated that mutation or deletion of elements within this signaling pathway leads to developmental syndromes in humans that are associated with impaired cognitive function and autism. Here, we review recent studies that provide insight into the biological roles of the ERKs in the brain that may underlie the cognitive deficits seen in these syndromes.
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http://dx.doi.org/10.1016/j.neuron.2009.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3663441PMC
January 2009

Mouse and human phenotypes indicate a critical conserved role for ERK2 signaling in neural crest development.

Proc Natl Acad Sci U S A 2008 Nov 24;105(44):17115-20. Epub 2008 Oct 24.

Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA.

Disrupted ERK1/2 (MAPK3/MAPK1) MAPK signaling has been associated with several developmental syndromes in humans; however, mutations in ERK1 or ERK2 have not been described. We demonstrate haplo-insufficient ERK2 expression in patients with a novel approximately 1 Mb micro-deletion in distal 22q11.2, a region that includes ERK2. These patients exhibit conotruncal and craniofacial anomalies that arise from perturbation of neural crest development and exhibit defects comparable to the DiGeorge syndrome spectrum. Remarkably, these defects are replicated in mice by conditional inactivation of ERK2 in the developing neural crest. Inactivation of upstream elements of the ERK cascade (B-Raf and C-Raf, MEK1 and MEK2) or a downstream effector, the transcription factor serum response factor resulted in analogous developmental defects. Our findings demonstrate that mammalian neural crest development is critically dependent on a RAF/MEK/ERK/serum response factor signaling pathway and suggest that the craniofacial and cardiac outflow tract defects observed in patients with a distal 22q11.2 micro-deletion are explained by deficiencies in neural crest autonomous ERK2 signaling.
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http://dx.doi.org/10.1073/pnas.0805239105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2579387PMC
November 2008

Deletion of ERK2 mitogen-activated protein kinase identifies its key roles in cortical neurogenesis and cognitive function.

J Neurosci 2008 Jul;28(27):6983-95

Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106-4928, USA.

The mitogen-activated protein (MAP) kinases ERK1 and ERK2 are critical intracellular signaling intermediates; however, little is known about their isoform-specific functions in vivo. We have examined the role of ERK2 in neural development by conditional inactivation of the murine mapk1/ERK2 gene in neural progenitor cells of the developing cortex. ERK MAP kinase (MAPK) activity in neural progenitor cells is required for neuronal cell fate determination. Loss of ERK2 resulted in a reduction in cortical thickness attributable to impaired proliferation of neural progenitors during the neurogenic period and the generation of fewer neurons. Mutant neural progenitor cells remained in an undifferentiated state until gliogenic stimuli induced their differentiation, resulting in the generation of more astrocytes. The mutant mice displayed profound deficits in associative learning. Importantly, we have identified patients with a 1 Mb microdeletion on chromosome 22q11.2 encompassing the MAPK1/ERK2 gene. These children, who have reduced ERK2 levels, exhibit microcephaly, impaired cognition, and developmental delay. These findings demonstrate an important role for ERK2 in cellular proliferation and differentiation during neural development as well as in cognition and memory formation.
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http://dx.doi.org/10.1523/JNEUROSCI.0679-08.2008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4364995PMC
July 2008

Intracytoplasmic sperm injection (ICSI) with transmission of a ring(Y) chromosome and ovotesticular disorder of sex development in offspring.

Am J Med Genet A 2008 Jul;146A(14):1828-31

Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.

We present a newborn infant with ovotesticular disorder of sex development and sex chromosome mosaicism with a supernumerary ring(Y), and a normal female cell line (47,XXr(Y)[10]/46,XX[40]. The ring (Y) was inherited from the child's father, and was transmitted following assisted reproductive technology and intracytoplasmic sperm injection (ICSI). The father presented with infertility and oligospermia, but cytogenetic analysis had not been carried out as part of the infertility workup. The Y containing cell line had not been seen on amniocentesis, which had shown a 46,XX apparently normal female karyotype in all cells studied. Molecular analysis using polymorphic probes from the X chromosome demonstrated that the 47,XXr(Y) cell line in the child was consistent with inheritance from the father, following meiosis I paternal non-disjunction. This report underscores the need to obtain chromosome analysis in couples with infertility who undergo assisted reproduction.
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http://dx.doi.org/10.1002/ajmg.a.32358DOI Listing
July 2008

Neuroimaging findings in macrocephaly-capillary malformation: a longitudinal study of 17 patients.

Am J Med Genet A 2007 Dec;143A(24):2981-3008

Cedars-Sinai Medical Center, Los Angeles, California, USA.

Here, we report the neuroimaging findings and neurological changes in 17 unpublished patients with Macrocephaly-Capillary Malformation (M-CM). This syndrome has been traditionally known as Macrocephaly-Cutis Marmorata Telangiectatica Congenita (M-CMTC), but we explain why M-CM is a more accurate term for this overgrowth syndrome. We analyzed the 17 patients with available brain MRI or CT scans and compared their findings with features identified by a comprehensive review of published cases. White matter irregularities with increased signal on T2-weighted images were commonly observed findings. A distinctive feature in more than half the patients was cerebellar tonsillar herniation associated with rapid brain growth and progressive crowding of the posterior fossa during infancy. In four such cases, we confirmed that the tonsillar herniation was an acquired event. Concurrently, with the development of these findings, ventriculomegaly (frequently obstructive) and dilated dural venous sinuses were observed in conjunction with prominent Virchow-Robin spaces in many of those in whom cerebellar tonsil herniation had developed. We postulate that this constellation of unusual features suggests a dynamic process of mechanical compromise in the posterior fossa, perhaps initiated by a rapidly growing cerebellum, which leads to congestion of the venous drainage with subsequently compromised cerebrospinal fluid reabsorption, all of which increases the posterior fossa pressure and leads to acquired tonsillar herniation. We make a distinction between congenital Chiari I malformation and acquired cerebellar tonsil herniation in this syndrome. We also observed numerous examples of abnormal cortical morphogenesis, including focal cortical dysplasia, polymicrogyria which primarily involved the perisylvian and insular regions, and cerebral and/or cerebellar asymmetric overgrowth. Other findings included a high frequency of cavum septum pellucidum or vergae, thickened corpus callosum, prominent optic nerve sheaths and a single case of venous sinus thrombosis. One patient was found to have a frontal perifalcine mass resembling a meningioma at age 5 years. This is the second apparent occurrence of this specific tumor in M-CM.
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http://dx.doi.org/10.1002/ajmg.a.32040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816457PMC
December 2007

From microscopes to microarrays: dissecting recurrent chromosomal rearrangements.

Nat Rev Genet 2007 Nov;8(11):869-83

Division of Human Genetics, The Children's Hospital of Philadelphia, Abramson Research Center, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Philadelphia 19104-4318, USA.

Submicroscopic chromosomal rearrangements that lead to copy-number changes have been shown to underlie distinctive and recognizable clinical phenotypes. The sensitivity to detect copy-number variation has escalated with the advent of array comparative genomic hybridization (CGH), including BAC and oligonucleotide-based platforms. Coupled with improved assemblies and annotation of genome sequence data, these technologies are facilitating the identification of new syndromes that are associated with submicroscopic genomic changes. Their characterization reveals the role of genome architecture in the aetiology of many clinical disorders. We review a group of genomic disorders that are mediated by segmental duplications, emphasizing the impact that high-throughput detection methods and the availability of the human genome sequence have had on their dissection and diagnosis.
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http://dx.doi.org/10.1038/nrg2136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2858421PMC
November 2007