Macrocephaly / Overgrowth Syndrome Panel

SEQmethod-seq-icon Our Sequence Analysis is based on a proprietary targeted sequencing method OS-Seq™ and offers panels targeted for genes associated with certain phenotypes. A standard way to analyze NGS data for finding the genetic cause for Mendelian disorders. Results in 21 days. DEL/DUPmethod-dup-icon Targeted Del/Dup (CNV) analysis is used to detect bigger disease causing deletions or duplications from the disease-associated genes. Results in 21 days. PLUSmethod-plus-icon Plus Analysis combines Sequence + Del/Dup (CNV) Analysis providing increased diagnostic yield in certain clinical conditions, where the underlying genetic defect may be detectable by either of the analysis methods. Results in 21 days.

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).


Results in 3-4 weeks.

Genes in the Macrocephaly / Overgrowth Syndrome Panel and their clinical significance
GeneAssociated phenotypesInheritanceClinVarHGMD
ABCC6*Pseudoxanthoma elasticumAD/AR/Digenic39285
AKT1Proteus syndrome, Cowden syndromeAD39
AKT3Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndromeAD821
ASPAAspartoacylase deficiency (Canavan disease)AR1990
BRWD3Mental retardationXL69
CCND2Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndromeAD710
CDKN1CBeckwith-Wiedemann syndrome, IMAGE syndromeAD2579
CUL4BMental retardation, syndromic, CabezasXL934
DIS3L2*Perlman syndromeAR69
DNMT3ATatton-Brown-Rahman syndromeAD1118
EIF2B5Leukoencephalopathy with vanishing white matter, OvarioleukodystrophyAR1495
EZH2Weaver syndromeAD1436
GFAPAlexander diseaseAD110112
GLI3Acrocallosal syndrome, Pallister-Hall syndrome, Grieg cephalopolysndactyly syndromeAD49221
GPC3Simpson-Golabi-Behmel syndromeXL2265
GPSM2Deafness, Chudley-McCullough syndromeAR1011
GRIA3Mental retardationXL917
HEPACAMMegalencephalic leukoencephalopathy with subcortical cysts, remittingAD/AR923
HUWE1Mental retardation, syndromic, TurnerXL831
KIAA0196Spastic paraplegia, Ritscher-Schinzel syndrome (3C syndrome)AD/AR714
KIF7Acrocallosal syndrome, Hydrolethalus syndrome, Al-Gazali-Bakalinova syndrome, Joubert syndromeAR/Digenic1339
L1CAMMental retardation, aphasia, shuffling gait, and adducted thumbs (MASA) syndrome, Hydrocephalus due to congenital stenosis of aqueduct of Sylvius, Spastic, CRASH syndrome, Corpus callosum, partial agenesisXL37286
MED12Ohdo syndrome, Mental retardation, with Marfanoid habitus, FG syndrome, Opitz-Kaveggia syndrome, Lujan-Fryns syndromeXL1719
MLC1Megalencephalic leukoencephalopathy with subcortical cystsAR17111
NSD1Sotos syndrome, Weaver syndrome, Beckwith-Wiedemann syndromeAD212461
OFD1Simpson-Golabi-Behmel syndrome, Retinitis pigmentosa, Orofaciodigital syndrome, Joubert syndromeXL129148
PIGA*Multiple congenital anomalies-hypotonia-seizures syndromeXL1914
PIK3CA*Cowden syndromeAD3044
PTCH1Basal cell nevus syndromeAD46348
PTEN*Bannayan-Riley-Ruvalcaba syndrome, Lhermitte-Duclos syndrome, Cowden syndromeAD192564
RAB39BWaisman parkinsonism-mental retardation syndrome, Mental retardationXL411
SYN1Epilepsy, with variable learning disabilities and behavior disordersXL75
TSC1Lymphangioleiomyomatosis, Tuberous sclerosisAD61306
TSC2Lymphangioleiomyomatosis, Tuberous sclerosisAD141977
UPF3BMental retardation, syndromicXL516
  • * 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 (; HGMD, refers to a number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD, The list of associated (gene specific) phenotypes are generated from CDG ( or Orphanet ( databases.

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.

Please see our latest validation report showing sensitivity and specificity for SNPs and indels, sequencing depth, % of the nucleotides reached at least 15x coverage etc. If the Panel is not present in the report, data will be published when the Panel becomes available for ordering. 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. All the Panels available for ordering have sensitivity and specificity higher than > 0.99 to detect single nucleotide polymorphisms and a high sensitivity for indels ranging 1-19 bp. 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. Detection limit for Del/Dup analysis varies through the genome from one to six exon Del/Dups depending on exon size, sequencing coverage and sequence content.

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 (, the NHLBI GO Exome Sequencing Project (ESP;, the Exome Aggregation Consortium (ExAC;, ClinVar database of genotype-phenotype associations ( and the Human Gene Mutation Database ( The consequence of variants in coding and splice regions are estimated using the following in silico variant prediction tools: SIFT (, Polyphen (, and Mutation Taster (

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


ICD codes

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

Q87.3Congenital 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.