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  • Test code: 04501
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit
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Invitae Overgrowth and Macrocephaly Syndromes Panel

Test description

The Invitae Overgrowth and Macrocephaly Syndromes Panel analyzes up to 26 genes that are associated with overgrowth and macrocephaly syndromes, which are characterized by extreme overgrowth (> 2 standard deviations) in weight and/or length. The growth may be symmetric, or localized to specific areas of the body, such as in macrocephaly or hemihypertrophy, respectively. Many of these syndromes are associated with increased risk of cancer. These genes were selected based on the available evidence to date to provide Invitae’s broadest test for overgrowth and macrocephaly syndromes.

Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant can inform recurrence-risk assessment and genetic counseling.

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Primary panel (21 genes)

AKT2 AKT3 CDKN1C CUL4B DIS3L2 DNMT3A EZH2 GLI3 GPC3 KPTN MED12 MTOR NF1 NFIX NPR2 NSD1 PHF6 PIK3R2 PTEN SETD2 SPRED1

Add-on Preliminary-evidence Genes for Overgrowth and Macrocephaly Syndromes (5 genes)

In addition to the primary panel, clinicians can also choose to include four genes that have preliminary evidence of association with overgrowth and macrocephaly. At this time, the association of these four genes with overgrowth and macrocephaly remains preliminary. However, some clinicians may wish to include genes that may prove to be clinically significant in the future. Visit our Preliminary-evidence genes page to learn more. These genes can be added at no additional charge.

DICER1 EED PDGFRB RNF125 UPF3B

Alternative tests to consider

Proteus syndrome is an overgrowth syndrome that is characterized by a mosaic AKT1 mutation, c.49G>A (p.Glu17Lys). The clinical sensitivity for Proteus syndrome is calculated based on the identification of this single known somatic mosaic pathogenic AKT1 variant in individuals meeting diagnostic criteria (PMID: 23992099). The sensitivity for detecting a pathogenic variant derived from a blood specimen in an individual with Proteus syndrome is unknown; as Proteus syndrome is hypothesized to be lethal if present in the germline. For additional information on ordering this test, please see the Invitae Proteus Syndrome Test page.

Please note, that the recommended specimen type for the Invitae Proteus syndrome test is extracted DNA; however, deletion/duplication analysis is not guaranteed with this specimen type if considering both the Invitae Overgrowth and Macrocephaly Panel and the Invitae Proteus syndrome test. If both tests are clinically indicated, it is recommended to submit two test requisitions and two sample types (extracted DNA and blood). Additional charges apply.

  • Bannayan-Riley-Ruvalcaba syndrome
  • Beckwith-Wiedemann syndrome
  • Borjeson-Forssman-Lehmann syndrome
  • Cabezas/Intellectual disability syndrome with central obesity, macrocephaly and macrosomic features
  • epiphyseal chondrodysplasia, Miura type (ECDM)
  • Greig cephalopolysyndactyly syndrome
  • hypoinsulinemic hypoglycemia with hemihypertrophy
  • Legius syndrome
  • Lujan-Fryns syndrome
  • Luscan-Lumish syndrome
  • megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome type 1
  • megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome type 2
  • neurofibromatosis, type 1
  • Pallister-Hall syndrome
  • Perlman syndrome
  • Simpson-Golabi-Behmel syndrome
  • Smith-Kingsmore syndrome
  • Sotos syndrome
  • Sotos-like/Marshall-Smith syndrome
  • Tatton-Brown-Rahman syndrome
  • Weaver syndrome

The Invitae Overgrowth and Macrocephaly Syndromes panel is intended to aid in the identification of a possible genetic cause for patients who present with a set of symptoms that include abnormal excessive height and/or weight and/or macrocephaly (>2 standard deviations). Onset may be prenatal or postnatal. Overgrowth may manifest in a symmetric or asymmetric pattern, and may include additional features such as developmental delay, intellectual disability, seizures, behavioral abnormalities, and dysmorphic features. Increased risk of cancer is commonly associated with many of these syndromes.

Clinical sensitivity is unknown across all of these conditions, as several are very rare or newly described and the incidence is not yet well established. For the more well-recognized conditions, such as Sotos, Legius, Neurofibromatosis, Weaver, Pallister-Hall, Simpson-Golabi-Behmel, and Perlman syndromes, clinical sensitivity is >80% for each condition. Because a high percentage of Beckwith-Wiedemann is caused by imprinting changes that are not detected by this assay, the sensitivity is only 40%.

GenePrevalencePenetranceClinical sensitivityInheritanceCondition
AKT2 rare, unknown unknown unknown AD Hypoinsulinemic hypoglycemia with hemihypertrophy
AKT3 rare, unknown unknown unknown AD/de novo Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2
CDKN1C 1:10,000 to 1:13,700 near 100% 40% AD/imprinting Beckwith Wiedemann syndrome
CUL4B rare, unknown near 100% unknown XL Cabezas, ID with central obesity, macrocephaly and macrosomic features
DIS3L2 rare, unknown unknown unknown AR Perlman syndrome
DNMT3A unknown unknown unknown AD/de novo Tatton-Brown-Rahman syndrome
EZH2 unknown unknown unknown AD Weaver syndrome
GPC3 unknown >70% unknown XL Simpson-Golabi-Behmel syndrome
KPTN unknown unknown unknown AD ID with macrocephaly
GLI3 rare unknown 80-95% AD Pallister-Hall syndrome, Greig Cephalopolysyndactyly syndrome
MED12 unknown near 100% unknown XL Lujan-Fryns syndrome, multiple
NF1 1:3000 near 100% >95% AD Neurofibromatosis, type 1
NFIX unknown near 100% unknown AD Sotos-like, Marshall-Smith syndromes
NPR2 unknown unknown unknown AD Epiphyseal chondrodysplasia, Miura type (ECDM)
NSD1 1:10,000 to 14,000 near 100% 27-93% AD Sotos syndrome
PHF6 unknown, rare unknown unknown XL Borjeson-Forssman-Lehmann syndrome
PTEN unknown near 100% 70% AD Bannayan-Riley-Ruvalcaba, Proteus syndrome
PIK3R2 unknown unknown unknown AD Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1
SETD2 unknown near 100% unknown AD Luscan Lumish syndrome
SPRED1 rare near 100% unknown AD Legius syndrome
MTOR unknown unknown unknown AD Smith-Kingsmore syndrome

These conditions are primarily inherited in an autosomal dominant pattern. Some genes are associated with X-linked inheritance. See summary table under Clinical Sensitivity for details.

This panel represents a heterogeneous set of conditions that have overlap in presentation. The individual gene/disease relationships may not all have the same level of penetrance, however penetrance is estimated to be near 100% for the conditions listed here. See summary table under Clinical Sensitivity for details.

The prevalence of these conditions is variable, and for many conditions, is unknown. However, majority of these conditions are considered so rare that their individual prevalence is unknown. See summary table under Clinical Sensitivity for details.

  1. Tatton-Brown, K, et al. Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability. Nat. Genet. 2014; 46(4):385-8. PMID: 24614070
  2. Astuti, D, et al. Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility. Nat. Genet. 2012; 44(3):277-84. PMID: 22306653
  3. Tarpey, PS, et al. Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit, cause an X-linked mental retardation syndrome associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus, and tremor. Am. J. Hum. Genet. 2007; 80(2):345-52. PMID: 17236139
  4. Mirzaa, GM, et al. Megalencephaly syndromes and activating mutations in the PI3K-AKT pathway: MPPH and MCAP. Am J Med Genet C Semin Med Genet. 2013; 163C(2):122-30. PMID: 23592320
  5. Kinross, KM, et al. Ubiquitous expression of the Pik3caH1047R mutation promotes hypoglycemia, hypoinsulinemia, and organomegaly. FASEB J. 2015; 29(4):1426-34. PMID: 25550458
  6. Morris, MR, et al. Perlman syndrome: overgrowth, Wilms tumor predisposition and DIS3L2. Am J Med Genet C Semin Med Genet. 2013; 163C(2):106-13. PMID: 23613427
  7. Tatton-Brown, K, Weksberg, R. Molecular mechanisms of childhood overgrowth. Am J Med Genet C Semin Med Genet. 2013; 163C(2):71-5. PMID: 23606607
  8. Cohen, AS, et al. A novel mutation in EED associated with overgrowth. J. Hum. Genet. 2015; 60(6):339-42. PMID: 25787343
  9. Biesecker, LG. Pallister-Hall Syndrome. 2000 May 25. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301638
  10. Sajorda BJ, et al. Simpson-Golabi-Behmel Syndrome Type 1. 2006 Dec 19. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1219/ PMID: 20301398
  11. Pajusalu, S, et al. Novel homozygous mutation in KPTN gene causing a familial intellectual disability-macrocephaly syndrome. Am. J. Med. Genet. A. 2015; 167(8):1913-5. PMID: 25847626
  12. Lyons, MJ. MED12-Related Disorders. 2008 Jun 23. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1676/ PMID: 20301719
  13. Tatton-Brown, K, Rahman, N. EZH2-Related Overgrowth. 2013 Jul 18. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 23865096
  14. Martinez, F, et al. Novel mutations of NFIX gene causing Marshall-Smith syndrome or Sotos-like syndrome: one gene, two phenotypes. Pediatr. Res. 2015; :None. PMID: 26200704
  15. Miura, K, et al. An overgrowth disorder associated with excessive production of cGMP due to a gain-of-function mutation of the natriuretic peptide receptor 2 gene. PLoS ONE. 2012; 7(8):e42180. PMID: 22870295
  16. Tatton-Brown, K, et al. Sotos Syndrome. 2004 Dec 17. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1479/ PMID: 20301652
  17. Gécz, J, et al. The Börjeson-Forssman-Lehman syndrome (BFLS, MIM #301900). Eur. J. Hum. Genet. 2006; 14(12):1233-7. PMID: 16912705
  18. Mirzaa, G, et al. PIK3CA-Related Segmental Overgrowth. 2013 Aug 15. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 23946963
  19. Eng, C. PTEN Hamartoma Tumor Syndrome (PHTS). 2001 Nov 29. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1488/ PMID: 20301661
  20. Luscan, A, et al. Mutations in SETD2 cause a novel overgrowth condition. J. Med. Genet. 2014; 51(8):512-7. PMID: 24852293
  21. Stevenson, D, et al. Legius Syndrome. 2010 Oct 14. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK47312/ PMID: 20945555
  22. Cohen, MM. Proteus syndrome review: molecular, clinical, and pathologic features. Clin. Genet. 2014; 85(2):111-9. PMID: 23992099
  23. Mroske, C, et al. Germline activating MTOR mutation arising through gonadal mosaicism in two brothers with megalencephaly and neurodevelopmental abnormalities. BMC Med. Genet. 2015; 16:102. PMID: 26542245
  24. Mirzaa, GM, et al. Association of MTOR Mutations With Developmental Brain Disorders, Including Megalencephaly, Focal Cortical Dysplasia, and Pigmentary Mosaicism. JAMA Neurol. 2016; 73(7):836-845. PMID: 27159400

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
AKT2 NM_001626.5
AKT3 NM_005465.4
CDKN1C NM_000076.2
CUL4B NM_003588.3
DICER1 NM_177438.2
DIS3L2 NM_152383.4
DNMT3A NM_175629.2
EED NM_003797.4
EZH2 NM_004456.4
GLI3 NM_000168.5
GPC3 NM_004484.3
KPTN NM_007059.3
MED12 NM_005120.2
MTOR NM_004958.3
NF1 NM_000267.3
NFIX NM_001271043.2
NPR2 NM_003995.3
NSD1 NM_022455.4
PDGFRB NM_002609.3
PHF6 NM_032458.2
PIK3R2 NM_005027.3
PTEN* NM_000314.4
RNF125 NM_017831.3
SETD2 NM_014159.6
SPRED1 NM_152594.2
UPF3B* NM_080632.2

PTEN: Deletion/duplication analysis covers the promoter region.
UPF3B: Deletion/duplication analysis is not offered for exons 2-3.