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NEURODEVELOPMENT NEXT-GENERATION SEQUENCING PANELS Mail: One Gustave L. Levy Place, Box 1497 CLIA #: 33D2097541 Specimens: 1428 Madison Ave, Atran Bldg, T: 800-298-6470 Page 1 of 125 Rm 2-25 New York, NY 10029 F: 212-241-0139 www.sema4genomics.com Mail: One Gustave L. Levy Place, Box 1497 CLIA #: 33D2097541 Specimens: 1428 Madison Ave, Atran Bldg, T: 800-298-6470 Page 2 of 125 Rm 2-25 New York, NY 10029 F: 212-241-0139 www.sema4genomics.com Mail: One Gustave L. Levy Place, Box 1497 CLIA #: 33D2097541 Specimens: 1428 Madison Ave, Atran Bldg, T: 800-298-6470 Page 3 of 125 Rm 2-25 New York, NY 10029 F: 212-241-0139 www.sema4genomics.com TABLE OF CONTENTS GENETIC TESTING FOR NEURODEVELOPMENTAL DISEASE 5 GENETICS 5 INDICATIONS 5 TESTING METHODS, SENSITIVITY, AND LIMITATIONS 6 TURNAROUND TIME 8 SPECIMEN AND SHIPPING REQUIREMENTS 8 CUSTOMER SERVICES AND GENETIC COUNSELING 9 THE COMPREHENSIVE EPILEPSY AND AUTISM PANEL 10 THE COMPREHENSIVE EPILEPSY PANEL 32 FOCAL, GENERALIZED, AND MYOCLONIC EPILEPSY SUBPANEL 48 INFANTILE EPILEPSY SUBPANEL 52 MIGRAINE SUBPANEL 56 NEURONAL CEROID LIPOFUSCINOSES SUBPANEL 57 NEURONAL MIGRATION SUBPANEL 58 SYNDROMIC EPILEPSY AND INTELLECTUAL DISABILITY SUBPANEL 61 THE COMPREHENSIVE AUTISM SPECTRUM DISORDER PANEL 67 STAT AUTISM SPECTRUM DISORDER SUBPANEL 80 MICROCEPHALY PANEL 84 REFERENCES 89 DISCLAIMER 108 Mail: One Gustave L. Levy Place, Box 1497 CLIA #: 33D2097541 Specimens: 1428 Madison Ave, Atran Bldg, T: 800-298-6470 Page 4 of 125 Rm 2-25 New York, NY 10029 F: 212-241-0139 www.sema4genomics.com Genetic Testing for NEURODEVELOPMENTAL DISEASE Sema4 offers targeted next-generation sequencing (NGS) for neurodevelopmental conditions such as autism spectrum disorder, Intellectual disability, epilepsy, seizures, brain malformations, and microcephaly. NGS technology is ideal for diagnostic testing of these disorders due to the extreme locus heterogeneity and phenotypic overlap of the genes involved. Our customizable targeted NGS panel uses Agilent SureSelectTM QXT target enrichment and Illumina NovaSeq sequencing to detect pathogenic variants in genes involved in neurodevelopmental disease. Sema4 offers three primary neurodevelopmental panels: 1) the Comprehensive Epilepsy and Autism Panel (401 genes); and 2) the Microcephaly Panel (78). The Comprehensive Epilepsy and Autism Panel includes the Comprehensive Autism Spectrum Disorder (ASD) Panel (228) and the Comprehensive Epilepsy (226) panels. The Comprehensive Autism Spectrum Disorder Panel includes the STAT Autism Panel (30 genes). The Comprehensive Epilepsy Panel includes the Focal, Generalized, and Myoclonic Epilepsy (52), Infantile Epilepsy (58), Migraine (7), Neuronal Migration (22), Neuronal Ceroid Lipofuscinoses (9), and the Syndromic Epilepsy and Intellectual Disability (ID; 93) Subpanels. The Microcephaly Panel includes conditions such as microcephaly, holoprosencephaly, lisencephaly, and other brain malformations for differential diagnosis. These genes were selected for inclusion based on literature review, clinical actionability scores, and comparison with commercially available assays. Further information about these genes and panels is available in the following pages. Customizable testing is available for ordering a neurodevelopment disease group-specific gene panel. Targeted familial testing for a specific variant is also available. Parental testing is recommended. Sema4 offers whole exome sequencing if needed. Genetic testing may clarify the cause of an individual’s neurodevelopmental disease, provide information on the likelihood of related health issues, and also establish risk to other family members and future generations. The American College of Medical Genetics (ACMG) recommends that every person with developmental delay, ID, or ASD should receive a chromosomal microarray (CMA) to identify copy number variants (CNVs) that contribute to risk in 10-15% of individuals. Sema4 offers CMA testing as a first-tier test and an ultra-high resolution medical exome array for exon-level CNV detection as an add-on to NGS. Genetics The disorders included in this panel may be inherited in an autosomal dominant (AD), autosomal recessive (AR), -linked (XL), or isolated cases (IC) manner. For genes displaying an AD mode of inheritance, an affected parent carrying the mutated gene has a 50% chance of passing the variant on to an offspring, regardless of gender. Some of these genes are not fully penetrant, meaning that an individual may have a mutated gene but not display any of the signs/symptoms of the disorder. Additionally, these disorders may have variable expressivity indicating that individuals carrying the same pathogenic variant may display differing features and/or differing severity. For diseases with AR inheritance, the risk for a couple who are both carriers to have a child affected with the disease is 25% for each pregnancy. The parents of an affected child are most often obligate carriers (heterozygotes) and each carry one mutant allele (unless a de novo mutation occurs). An X-linked inheritance means that the risk of a male offspring with the disorder will be 50% if the mother carries an XL mutation. Depending on the X- inactivation pattern of the gene, a mother and her daughters may rarely be affected. Although X-linked diseases are normally transmitted from mother to son, transmission of an X-linked mutation will occur from an affected father to each daughter, but will not occur from father to son. An IC mode of inheritance indicates no prior family history. Indications 1. Clinical status: to confirm a clinical diagnosis in an affected patient, in an individual with unknown status (no screening/evaluation), or in unaffected relatives of an affected patient (all screening/evaluations(s) normal). The purpose of the test may be diagnostic, carrier testing, familial follow-up on a known family variant, or prenatal testing for known variant(s). 2. Treatment: to clarify the cause of an individual’s neurodevelopmental disease, provide information on the likelihood of related health issues, and guide treatment. 3. Family risk: to establish risk to other family members and future generations. Mail: One Gustave L. Levy Place, Box 1497 CLIA #: 33D2097541 Specimens: 1428 Madison Ave, Atran Bldg, T: 800-298-6470 Page 5 of 125 Rm 2-25 New York, NY 10029 F: 212-241-0139 www.sema4genomics.com For patients with a suspected syndrome or disorder, please consider single gene sequencing or associated subpanels prior to ordering the comprehensive panel. Testing Methods, Sensitivity, and Limitations Next Generation Sequencing (NGS) (Analytical Detection Rate >95%) Agilent SureSelectTM QXT technology is used with a custom capture library to target the exonic regions and intron/exon splice junctions of the relevant genes, as well as a number of UTR, intronic or promoter regions that contain previously reported mutations. Samples are pooled and sequenced on the Illumina NovaSeq platform in the Xp workflow, using 100 bp paired- end reads. The sequencing data are analyzed using a custom bioinformatics algorithm designed and validated in-house. In our validation, average coverage was greater than 200X per sample with >99.9% of regions covered at greater than 20X. The coding exons and splice junctions of the known protein-coding RefSeq genes are assessed for the average depth of coverage (minimum of 20X) and data quality threshold values. Most exons not meeting a minimum of >20X read depth across the exon are further analyzed by Sanger sequencing. Please note that several genomic regions present difficulties in mapping or obtaining read depth >20X. These regions include, but are not limited to, UTRs, promoters, and deep intronic areas. In addition, a mutation(s) in a gene not included on the panel could be present in this patient. The following regions (hg19 coordinates) have been excluded due to lack of amenability to NGS or Sanger sequencing, high GC content, high homology, lack of known clinically significant variants, or overlap with repetitive regions: ALDH7A1 chr5:125907050-125907056, ARX chrX:25031027-25031926, ATP13A2 chr1:17338212-17338244, ATP2A2 chr12:110718408-110718414, ATP6AP2 chrX:40440306-40440365, ATP7A chrX:77269723-77269729, ATP7A chrX:77278955-77279156, ATR chr3:142184699- 142184705, CACNA1H chr16:1203726-1204047, CACNA2D2 chr3:50540637-50540865, CDKN1C chr11:2905888- 2906730, CHRNA7 chr15:32460129-32460670, CHRNA7 chr15:32446096-32446198, COL18A1 chr21:46825134- 46825167, COL18A1 chr21:46825282-46825399, DMD chrX:31897426-31897627, DMD chrX:32668999-32669253, DMD chrX:32644476-32644680, DMD chrX:31627637-31627838, DMD chrX:32460213-32460334, DMD chrX:31219361- 31219367, DMD chrX:31219126-31219287, DMD chrX:32644160-32644321, EHMT1 chr9:140513469-140513512, ELP4 chr11:31703323-31703634, EPM2A chr6:146056322-146056645, FKTN chr9:108368751-108368962, FMR1 chrX:147018844-147019305, GABRD chr1:1950851-1950941, GK chrX:30687487-30687493, HGSNAT chr8:42995524- 42995881, HPRT1 chrX:133625461-133625467, HTRA1 chr10:124221157-124221651, IDS chrX:148584720-148585050, IQSEC2 chrX:53263389-53264377, KRIT1 chr7:91829915-91829921, LAMP2 chrX:119604075-119604081, MAGI2 chr7:77648620-77649304, NFIX chr19:13106640-13106689, NHS chrX:17753589-17753595, NOTCH3 chr19:15311587- 15311727, OTC chrX:38269298-38269509, SCN1B chr19:35521713-35521775, SCN3A chr2:165986438-165986817, SGSH chr17:78193967-78194168, ST3GAL5 chr2:86115935-86116039, SYNGAP1 chr6:33388030-33388119, TBX1 chr22:19748416-19748814, TMLHE chrX:154721184-154721338, TMLHE chrX:154722214-154722372,
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  • MASA Syndrome in Twin Brothers: Case Report of Sixteen-Year Clinical Follow Up

    MASA Syndrome in Twin Brothers: Case Report of Sixteen-Year Clinical Follow Up

    Paediatr Croat. 2014;58:286-90 PRIKAZ BOLESNIKA / CASE REPORT www.paedcro.com http://dx.doi.org/10.13112/PC.2014.50 MASA syndrome in twin brothers: case report of sixteen-year clinical follow up Matilda Kovač Šižgorić1, Zlatko Sabol1, Filip Sabol2, Tonći Grmoja3, Svjetlana Bela Klancir1, Zdravka Gjergja1, Ljiljana Kipke Sabol1 MASA syndrome (OMIM 303350) is a rare X-linked recessive neurologic disorder, also called CRASH syndrome, spastic paraplegia 1 and Gareis-Mason syndrome. The acronym MASA describes four major signs: Mental retardation, Aphasia, Shuffl ing gait and Adducted thumbs. A more suitable name for this syndrome is L1 syndrome because the disorder has been associated with mutations in the neuronal cell adhesion molecule L1 (L1CAM) gene. The syndrome has severe symptoms in males, while females are carriers because only one X chromosome is aff ected. The aim of this report is to show similarities and diff erences in clinical manifestations between twins with the L1CAM gene mutation and to emphasize the importance of genetic counseling. Our patients were dizygotic twins born prematurely at 35 weeks of gestation. Pregnancy was complicated with early bleeding and gestational diabetes. Immediately after birth, hypertonia of lower extremities was observed in both twins. Sixteen-year clinical follow up showed spastic paraparetic form with shuffl ing gait, clumsiness, delayed speech development, lower intellectual functioning at the level of mild to moderate mental retarda- tion, primary nocturnal enuresis, behavioral and sleep disorder (more pronounced in the second twin). Magnetic resonance imaging of the brain showed complete agenesis of the corpus callosum, complete lack of the anterior commissure, and internal hydrocephalus.