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.
PTEN: Deletion/duplication analysis covers the promoter region.
AKT2 AKT3 CDKN1C CUL4B DIS3L2 DNMT3A EZH2 GLI3 GPC3 KPTN MED12 MTOR NF1 NFIX NPR2 NSD1 PHF6 PIK3R2 PTEN SETD2 SPRED1
DICER1 EED PDGFRB RNF125 UPF3B
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.
AKT2 AKT3 CDKN1C CUL4B DIS3L2 DNMT3A EZH2 GLI3 GPC3 KPTN MED12 MTOR NF1 NFIX NPR2 NSD1 PHF6 PIK3R2 PTEN SETD2 SPRED1
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
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.
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%.
Gene | Prevalence | Penetrance | Clinical sensitivity | Inheritance | Condition |
---|---|---|---|---|---|
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.
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 and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.
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 |
DICER1: Sequencing analysis for exons 22 includes only cds +/- 10 bp.
EZH2: Sequencing analysis for exon 20 is limited to cds +/-10 bp.
GPC3: Sequencing analysis for exon 3 is limited to cds +/-10 bp.
NF1: Sequencing analysis for exons 2, 7, 25, 41, 48 includes only cds +/- 10 bp.
PTEN: Deletion/duplication analysis covers the promoter region. Sequencing analysis for exons 8 includes only cds +/- 10 bp.
UPF3B: Deletion/duplication analysis is not offered for exons 2-3.