Macrocephaly / Overgrowth Syndrome Panel

  • bpg-method PLUS
  • bpg-method SEQ
  • bpg-method DEL/DUP

Test code: MA1401

The Blueprint Genetics Macrocephaly / Overgrowth Syndrome Panel is a 38 gene test for genetic diagnostics of patients with clinical suspicion of congenital malformation syndromes involving early overgrowth or macrocephaly.

Multiple genetic conditions are associated with macrocephaly and overgrowth syndromes and this panel can be used for their differential diagnostics. This Panel is part of Comprehensive Skeletal / Malformation Syndrome Panel.

About Macrocephaly / Overgrowth Syndrome

Macrocephaly is a condition in which the head is abnormally large (circumference 2.5 standard deviations above normal for weight and gender) inclusive of the scalp, the cranial bone, and intracranial contents. Many people with an unusually large head and large skull are healthy, however macrocephaly may be pathologic. Macrocephaly may be due to megalencephaly (true enlargement of the brain) or due to other conditions such as hydrocephalus or cranial thickening, and is a common reason for referral to genetics clinic. Macrocephaly is associated with many genetic disorders. Syndromic and nonsyndromic forms of pathologic macrocephaly may be caused by congenital anatomic abnormalities or genetic conditions, but the disease may also be nongenetic and caused by environmental events. The genetic macrocephaly conditions cover a broad spectrum of gene disorders and their related proteins have diverse biological functions. As of yet it is not clear what precise biological pathways lead to generalized brain overgrowth, but several genes have been identified. Genetics databases list 164 conditions, including 17 metabolic disorders, associated with macrocephaly. Genetic types of macrocephaly include: 1) familial macrocephaly (benign asymptomatic), 2) autism disorder (multifactorial, non-syndromic type), 3) syndrome associations (multiple types) 3A) with cutaneous findings (PTEN hamartoma syndromes, neurofibromatosis, type 1 hemimegalencephaly), 3B) with overgrowth (Sotos, Weaver, Macrocephaly-Cutis Marmorata Telangiectasia Congenita, Simpson-Golabi-Behmel, Beckwith-Wiedemann Syndrome), 3C) neuro-cardio-facial-cutaneous syndromes (Noonan, Costello, Cardiofaciocutaneous (CFC), LEOPARD), 3D) with mental retardation (Fragile X syndromes), 4) metabolic types with leukodystrophy (Alexander; Canavan, megalencephalic leukodystrophy, organic acidurias, glutaric aciduria, type 1, D-2-hydroxyglutaric aciduria and 5) hydrocephalus (aqueductal stenosis types and multifactorial, non-obstructive types).

Availability

Results in 3-4 weeks. We do not offer a maternal cell contamination (MCC) test at the moment. We offer prenatal testing only for cases where the maternal cell contamination studies (MCC) are done by a local genetic laboratory. Read more: http://blueprintgenetics.com/faqs/#prenatal

Genes in the Macrocephaly / Overgrowth Syndrome Panel and their clinical significance
Gene Associated phenotypes Inheritance ClinVar HGMD
ABCC6* Pseudoxanthoma elasticum AR 39 285
AKT1 Proteus syndrome, Cowden syndrome AD 3 9
AKT3 Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome AD 8 21
ASPA Aspartoacylase deficiency (Canavan disease) AR 19 90
BRWD3 Mental retardation XL 6 9
CCND2 Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome AD 7 10
CDKN1C Beckwith-Wiedemann syndrome, IMAGE syndrome AD 25 79
CHD8 Autism AD 10 37
CUL4B Mental retardation, syndromic, Cabezas XL 9 34
DHCR24 Desmosterolosis AR 6 8
DIS3L2* Perlman syndrome AR 6 9
DNMT3A Tatton-Brown-Rahman syndrome AD 11 18
EIF2B5 Leukoencephalopathy with vanishing white matter, Ovarioleukodystrophy AR 14 95
EZH2 Weaver syndrome AD 14 36
GFAP Alexander disease AD 110 112
GLI3 Acrocallosal syndrome, Pallister-Hall syndrome, Grieg cephalopolysndactyly syndrome, Postaxial polydactyly type A, Preaxial polydactyly type 3, Preaxial polydactyly type 4 AD 49 221
GPC3 Simpson-Golabi-Behmel syndrome XL 22 65
GPSM2 Deafness, Chudley-McCullough syndrome AR 10 11
GRIA3 Mental retardation XL 9 17
HEPACAM Megalencephalic leukoencephalopathy with subcortical cysts, remitting AD/AR 9 23
HUWE1 Mental retardation, syndromic, Turner XL 8 31
KIAA0196 Spastic paraplegia, Ritscher-Schinzel syndrome (3C syndrome) AD/AR 7 14
KIF7 Acrocallosal syndrome, Hydrolethalus syndrome, Al-Gazali-Bakalinova syndrome, Joubert syndrome AR/Digenic 13 39
L1CAM Mental retardation, aphasia, shuffling gait, and adducted thumbs (MASA) syndrome, Hydrocephalus due to congenital stenosis of aqueduct of Sylvius, Spastic, CRASH syndrome, Corpus callosum, partial agenesis XL 37 286
MED12 Ohdo syndrome, Mental retardation, with Marfanoid habitus, FG syndrome, Opitz-Kaveggia syndrome, Lujan-Fryns syndrome XL 17 19
MLC1 Megalencephalic leukoencephalopathy with subcortical cysts AR 17 111
NFIX Marshall-Smithsyndrome AD 27 51
NSD1 Sotos syndrome, Weaver syndrome, Beckwith-Wiedemann syndrome AD 212 461
OFD1 Simpson-Golabi-Behmel syndrome, Retinitis pigmentosa, Orofaciodigital syndrome, Joubert syndrome XL 129 148
PIGA* Multiple congenital anomalies-hypotonia-seizures syndrome XL 19 14
PIK3CA* Cowden syndrome, CLOVES AD 30 44
PTCH1 Basal cell nevus syndrome AD 46 348
PTEN* Bannayan-Riley-Ruvalcaba syndrome, Lhermitte-Duclos syndrome, Cowden syndrome AD 192 564
RAB39B Waisman parkinsonism-mental retardation syndrome, Mental retardation XL 4 11
SYN1 Epilepsy, with variable learning disabilities and behavior disorders XL 7 5
TSC1 Lymphangioleiomyomatosis, Tuberous sclerosis AD 61 306
TSC2 Lymphangioleiomyomatosis, Tuberous sclerosis AD 141 977
UPF3B Mental retardation, syndromic XL 5 16

*Some regions of the gene are duplicated in the genome leading to limited sensitivity within the regions. Thus, low-quality variants are filtered out from the duplicated regions and only high-quality variants confirmed by other methods are reported out. Read more.

Gene, refers to HGNC approved gene symbol; Inheritance to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL); ClinVar, refers to a number of variants in the gene classified as pathogenic or likely pathogenic in ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/); HGMD, refers to a number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD, http://www.hgmd.cf.ac.uk/ac/). The list of associated (gene specific) phenotypes are generated from CDG (http://research.nhgri.nih.gov/CGD/) or Orphanet (http://www.orpha.net/) databases.

Gene Genomic location HG19 HGVS RefSeq RS-number Comment Reference
L1CAM ChrX:153131293 c.2432-19A>C NM_000425.4
OFD1 ChrX:13773245 c.1130-22_1130-19delAATT NM_003611.2 rs312262865
OFD1 ChrX:13768358 c.935+706A>G NM_003611.2 rs730880283
PTEN Chr10:89623462 c.-765G>A NM_000314.4
PTEN Chr10:89623365 c.-862G>T NM_000314.4 rs587776675
TSC2 Chr16:2098067 c.-30+1G>C NM_000548.3 rs587778004

The strengths of this test include:

  • Blueprint Genetics is one of the few laboratories worldwide with CAP and ISO-15189 accreditation for NGS panels and CLIA certification
  • Superior sequencing quality
  • Careful selection of genes based on current literature, our experience and the most current mutation databases
  • Transparent and easy access to quality and performance data at the patient level that are accessible via our Nucleus portal
  • Transparent and reproducible analytical validation for each panel (see Test performance section; for complete details, see our Analytic Validation)
  • Sequencing and high resolution del/dup analysis available in one test
  • Inclusion of non-coding disease causing variants where clinically indicated (please see individual Panel descriptions)
  • Interpretation of variants following ACMG variant classification guidelines
  • Comprehensive clinical statement co-written by a PhD geneticist and a clinician specialist

 

This test does not detect the following:

  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Mitochondrial DNA variants
  • Variants in regulatory or non-coding regions of the gene unless otherwise indicated (please see Non-coding disease causing variants covered by the panel). This mean for instance intronic variants locating deeper than 15 nucleotides from the exon-intron boundary.

 

This test may not reliably detect the following:

  • Low level mosaicism
  • Stretches of mononucleotide repeats
  • Indels larger than 50bp
  • Single exon deletions or duplications
  • Variants within pseudogene regions/duplicated segments
  • Disorders caused by long repetitive sequences (e.g. trinucleotide repeat expansions)

 

The sensitivity of this test may be reduced if DNA is extracted by a laboratory other than Blueprint Genetics.

For additional information, please refer to the Test performance section and see our Analytic Validation.

Blueprint Genetics offers a comprehensive Macrocephaly / Overgrowth Syndrome Panel that covers classical genes associated with congenital malformation syndromes involving early overgrowth and macrocephaly. The genes are carefully selected based on the existing scientific evidence, our experience and most current mutation databases. Candidate genes are excluded from this first-line diagnostic test. The test does not recognise balanced translocations or complex inversions, and it may not detect low-level mosaicism. The test should not be used for analysis of sequence repeats or for diagnosis of disorders caused by mutations in the mitochondrial DNA.

Analytical validation is a continuous process at Blueprint Genetics. Our mission is to improve the quality of the sequencing process and each modification is followed by our standardized validation process. Average sensitivity and specificity in Blueprint NGS Panels is 99.3% and 99.9% for detecting SNPs. Sensitivity to for indels vary depending on the size of the alteration: 1-10bps (96.0%), 11-20 bps (88.4%) and 21-30 bps (66.7%). The longest detected indel was 46 bps by sequence analysis. Detection limit for Del/Dup (CNV) analysis varies through the genome depending on exon size, sequencing coverage and sequence content. The sensitivity is 71.5% for single exon deletions and duplications and 99% for three exons’ deletions and duplications. We have validated the assays for different starting materials including EDTA-blood, isolated DNA (no FFPE) and saliva that all provide high-quality results. The diagnostic yield varies substantially depending on the used assay, referring healthcare professional, hospital and country. Blueprint Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be cost-effective first line test if your patient’s phenotype is suggestive for a specific mutation profile.

The sequencing data generated in our laboratory is analyzed with our proprietary data analysis and annotation pipeline, integrating state-of-the art algorithms and industry-standard software solutions. Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. The highest relevance in the reported variants is achieved through elimination of false positive findings based on variability data for thousands of publicly available human reference sequences and validation against our in-house curated mutation database as well as the most current and relevant human mutation databases. Reference databases currently used are the 1000 Genomes Project (http://www.1000genomes.org), the NHLBI GO Exome Sequencing Project (ESP; http://evs.gs.washington.edu/EVS), the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org), ClinVar database of genotype-phenotype associations (http://www.ncbi.nlm.nih.gov/clinvar) and the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk). The consequence of variants in coding and splice regions are estimated using the following in silico variant prediction tools: SIFT (http://sift.jcvi.org), Polyphen (http://genetics.bwh.harvard.edu/pph2/), and Mutation Taster (http://www.mutationtaster.org).

Through our online ordering and statement reporting system, Nucleus, the customer can access specific details of the analysis of the patient. This includes coverage and quality specifications and other relevant information on the analysis. This represents our mission to build fully transparent diagnostics where the customer gains easy access to crucial details of the analysis process.

In addition to our cutting-edge patented sequencing technology and proprietary bioinformatics pipeline, we also provide the customers with the best-informed clinical report on the market. Clinical interpretation requires fundamental clinical and genetic understanding. At Blueprint Genetics our geneticists and clinicians, who together evaluate the results from the sequence analysis pipeline in the context of phenotype information provided in the requisition form, prepare the clinical statement. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals, even without training in genetics.

Variants reported in the statement are always classified using the Blueprint Genetics Variant Classification Scheme modified from the ACMG guidelines (Richards et al. 2015), which has been developed by evaluating existing literature, databases and with thousands of clinical cases analyzed in our laboratory. Variant classification forms the corner stone of clinical interpretation and following patient management decisions. Our statement also includes allele frequencies in reference populations and in silico predictions. We also provide PubMed IDs to the articles or submission numbers to public databases that have been used in the interpretation of the detected variants. In our conclusion, we summarize all the existing information and provide our rationale for the classification of the variant.

A final component of the analysis is the Sanger confirmation of the variants classified as likely pathogenic or pathogenic. This does not only bring confidence to the results obtained by our NGS solution but establishes the mutation specific test for family members. Sanger sequencing is also used occasionally with other variants reported in the statement. In the case of variant of uncertain significance (VUS) we do not recommend risk stratification based on the genetic finding. Furthermore, in the case VUS we do not recommend use of genetic information in patient management or genetic counseling. For some cases Blueprint Genetics offers a special free of charge service to investigate the role of identified VUS.

We constantly follow genetic literature adapting new relevant information and findings to our diagnostics. Relevant novel discoveries can be rapidly translated and adopted into our diagnostics without delay. These processes ensure that our diagnostic panels and clinical statements remain the most up-to-date on the market.

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ICD & CPT codes

CPT codes

SEQ 81479
DEL/DUP 81479


ICD codes

Commonly used ICD-10 codes when ordering the Macrocephaly / Overgrowth Syndrome Panel

ICD-10 Disease
Q75.3 Macrocephaly
Q87.3 Congenital malformation syndromes involving early overgrowth

Accepted sample types

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 5μg
  • Saliva (Oragene DNA OG-500 kit)

Label the sample tube with your patient’s name, date of birth and the date of sample collection.

Note that we do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue.

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