Overgrowth and Macrocephaly Syndromes Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
3449 ABCC9 81479,81479 Order Options and Pricing
AKT1 81479,81479
AKT2 81479,81479
AKT3 81479,81479
ANKH 81479,81479
ASPA 81479,81479
ASXL2 81479,81479
BRSK2 81479,81479
BRWD3 81479,81479
CCND2 81479,81479
CCNK 81479,81479
CDKN1C 81479,81479
CHD3 81479,81479
CHD8 81479,81479
CUL4B 81479,81479
D2HGDH 81479,81479
DICER1 81479,81479
DIS3L2 81479,81479
DNMT3A 81479,81479
DVL1 81479,81479
EED 81479,81479
EZH2 81236,81479
FBN1 81408,81479
FGFR3 81479,81479
FIBP 81479,81479
FOXP1 81479,81479
GATAD2B 81479,81479
GFAP 81405,81479
GLI3 81479,81479
GPC3 81479,81479
GPC4 81479,81479
GPSM2 81479,81479
H1-4 81479,81479
HEPACAM 81479,81479
HERC1 81479,81479
HRAS 81404,81479
HUWE1 81479,81479
KCNH1 81479,81479
KIF7 81479,81479
KMT2E 81479,81479
KPTN 81479,81479
KRAS 81405,81479
LBR 81479,81479
MED12 81479,81479
MLC1 81479,81479
MPDZ 81479,81479
MTOR 81479,81479
NF1 81408,81479
NFIA 81479,81479
NFIX 81479,81479
NPR2 81479,81479
NRAS 81479,81479
NSD1 81406,81405
ODC1 81479,81479
OFD1 81479,81479
PDGFRB 81479,81479
PHF21A 81479,81479
PHF6 81479,81479
PIGM 81479,81479
PIK3CA 81479,81479
PIK3R2 81479,81479
PPP1CB 81479,81479
PPP2R5B 81479,81479
PPP2R5C 81479,81479
PPP2R5D 81479,81479
PTCH1 81479,81479
PTEN 81321,81323
RAB39B 81479,81479
RIN2 81479,81479
RNF125 81479,81479
RNF135 81479,81479
SETD2 81479,81479
SHANK3 81479,81479
SOS1 81406,81479
SOST 81479,81479
STRADA 81479,81479
SUZ12 81479,81479
SZT2 81479,81479
TBC1D7 81479,81479
TGFB3 81479,81479
TMEM94 81479,81479
TRIP12 81479,81479
UPF3B 81479,81479
WNT5A 81479,81479
ZBTB20 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
3449Genes x (85)81479 81236, 81321, 81323, 81404, 81405, 81406, 81408, 81479 $990 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our PGxome Custom Panel tool.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

For Reflex to PGxome pricing click here.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Overgrowth and macrocephaly syndromes constitute a heterogeneous group of developmental disorders that share growth excess as a predominant clinical feature. The majority of the disorders in this group are extremely rare. This panel is designed to aid the molecular diagnosis of disorders with features of macrocephaly (occipitofrontal circumference >98 percentile) and/or overgrowth that may be generalized, segmental, symmetric, or asymmetric. Excess growth can occur as an isolated feature or as part of a multiple malformation syndrome. Frequently, overgrowth disorders are associated with developmental delay, intellectual disability, and seizures, and may predispose patients to certain cancers (Olney et al. 2007. PubMed ID: 17980309; Verge and Mowat. 2010. PubMed ID: 20371592).

The physiological mechanisms of overgrowth are diverse, involving an increase in cell number, cell volume, or tissue proliferation. In many of the overgrowth disorders, these defects occur early in development resulting in prenatal or neonatal onset. However, in some conditions growth excess may not be appreciated until childhood. This panel targets over 40 disorders that include excess growth as a prominent and early symptom of the disease.

There are currently no treatments for constitutional overgrowth syndromes. However, molecular diagnosis can provide valuable prognostic information for guiding clinical management particularly related to cancer surveillance (Mester and Eng. 2013. PubMed ID: 23613428, Neylon et al. 2012 PubMed ID: 22705997).

Genetics

The majority of overgrowth- and macrocephaly-related disorders are inherited in an autosomal dominant manner; however, recessive and X-linked inheritance is also observed. Many of the overgrowth syndromes are caused by activation (often loss of inhibition) of the PI3K/AKT/mTOR tyrosine receptor kinase pathway (AKT1, AKT2, AKT3, MTOR, PIK3CA, PIK3R2, PTEN, and TBC1D7), which plays a central role in cell growth and proliferation, angiogenesis, metabolism, and cell survival (Mester and Eng. 2013. PubMed ID: 23613428). Other molecular mechanisms involve the sonic hedgehog signaling pathway (GLI3, KIF7 and PTCH1) and cell cycle checkpoints (CCND2, CDKN1C, CUL4B, DIS3L2, HUWE1, OFD1, PPP2R5B, PPP2R5C, PPP2R5D, and STRADA) to name a few.

Due to the diverse functions of the genes involved, all varieties of pathogenic variants have been reported including, missense, nonsense, frameshift, gross deletions, and structural rearrangements (Human Genome Mutation Database). Pathogenic regulatory variants in the promoter of the PTEN gene have also been described. This test includes coverage of this clinically relevant region (from c.-700 to c.-1400). Among the conditions that are well characterized, penetrance is nearly 100%. For those that are dominant, de novo pathogenic variants are common. Finally, a subset of overgrowth conditions involve somatic mosaicism. This panel is not validated for detecting mosaic variants.

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

Clinical Sensitivity - Sequencing with CNV PGxome

The analytical sensitivity of this test for detecting small sequence variation is >99%. The clinical sensitivity for making a positive diagnosis will vary considerably depending on the condition involved. It is expected to be very high for the well-characterized recognizable syndromes that are predominantly caused by small sequence variants. Examples from the literature include Sotos syndrome (~90%; Saugier-Veber et al. 2007. PubMed ID: 17565729) and Bannayan-Riley-Ruvalcaba syndrome (~70%; Marsh et al. 1998. PubMed ID: 9467011). Conditions with less defining features, such as Weaver syndrome, are expected to have lower diagnostic rates (~5%; Tatton-Brown et al. 2011. PubMed ID: 22190405). Finally, the sensitivity for Beckwith Wiedmann syndrome will be low (~5%), since this disorder is predominantly caused by methylation defects (Shuman et al. 2016. PubMed ID: 20301568).

Testing Strategy

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides typically 99.2% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Indications for Test

This test is appropriate for individuals with clinical features that include macrocephaly (occipitofrontal circumference >98 percentile) or overgrowth that may be generalized, segmental, symmetric, or asymmetric. Importantly, this test is not validated for detecting mosaic variants with a low variant allele fraction, as expected in conditions such as Proteus syndrome (AKT1) and PIK3CA-related overgrowth syndromes (PIK3CA).

Diseases

Name Inheritance OMIM ID
Achondroplasia AD 100800
Acrocallosal Syndrome, Schinzel Type AR 200990
Acromesomelic Dysplasia Maroteaux Type AR 602875
Acromicric Dysplasia AD 102370
Al-Gazali-Bakalinova syndrome AR 607131
Alexander Disease AD 203450
Aml - Acute Myeloid Leukemia 601626
Arrhythmogenic Right Ventricular Cardiomyopathy, Type 1 AD 107970
Arteriovenous Malformations Of The Brain 108010
Autism, Susceptibility to, 18 AD 615032
Beckwith-Wiedemann Syndrome AD 130650
Bladder Cancer 109800
Borjeson-Forssman-Lehmann Syndrome XL 301900
Brain malformations with or without urinary tract defects AD 613735
Camptodactyly, Tall Stature, And Hearing Loss Syndrome AD 610474
Cardiofaciocutaneous syndrome 2 AD 615278
Cervical Cancer 603956
Chondrocalcinosis 2 AD 118600
Chudley-McCullough syndrome AR 604213
Cohen-Gibson syndrome AD 617561
Costello Syndrome AD 218040
Cowden Disease AD 158350
Cowden syndrome 5 AD 615108
Cowden syndrome 6 AD 615109
Craniodiaphyseal Dysplasia, Autosomal Dominant AD 122860
Craniometaphyseal Dysplasia, Autosomal Dominant AD 123000
Crouzon Syndrome With Acanthosis Nigricans AD 612247
D-2-Alpha Hydroxyglutaric Aciduria AR 600721
Ectopia Lentis, Isolated, Autosomal Dominant AD 129600
Epidermal Nevus 162900
Epileptic encephalopathy, early infantile, 18 AR 615476
Epiphyseal chondrodysplasia, Miura type AD 615923
Familial Cancer Of Breast 114480
Familial Colorectal Cancer 114500
Fg Syndrome XL 305450
Geleophysic Dysplasia 2 AD 614185
GLOW syndrome, somatic mosaic 618272
Glycosylphosphatidylinositol Deficiency AR 610293
Goiter, Multinodular 1, With Or Without Sertoli-Leydig Cell Tumors AD 138800
Gorlin Syndrome AD 109400
Greenberg Dysplasia AR 215140
Greig Cephalopolysyndactyly Syndrome AD 175700
Hereditary Diffuse Gastric Cancer 137215
Hereditary Gingival Fibromatosis AD 135300
Holoprosencephaly 7 AD 610828
Hydrocephalus, Nonsyndromic, Autosomal Recessive 2 AR 615219
Hyperphosphatasemia Tarda AR 239100
Hypertrichotic Osteochondrodysplasia AD 239850
Hypochondroplasia AD 146000
Hypoglycemia, Neonatal, Simulating Foetopathia Diabetica AD 240900
IMAGE Syndrome AD 614732
Intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures AD 618725
Intellectual developmental disorder with cardiac defects and dysmorphic facies AR 618316
Intellectual developmental disorder with hypertelorism and distinctive facies AD 618147
Joubert Syndrome 10 XL 300804
Juvenile Myelomonocytic Leukemia 607785
Keipert syndrome XL 301026
Kosaki overgrowth syndrome AD 616592
Lacrimoauriculodentodigital Syndrome AD 149730
Loeys-Dietz Syndrome 5 AD 615582
Lujan-Fryns Syndrome XL 309520
Lung Cancer 211980
Luscan-Lumish Syndrome AD 616831
Macrocephaly, Alopecia, Cutis Laxa, And Scoliosis AR 613075
Macrocephaly, dysmorphic facies, and psychomotor retardation AR 617011
Macrocephaly/Autism Syndrome AD 605309
Macrocephaly/megalencephaly syndrome, autosomal recessive AR 248000
Marfan lipodystrophy syndrome AD 616914
Marfan Syndrome AD 154700
Marshall-Smith Syndrome AD 602535
Mass Syndrome AD 604308
Megalencephalic Leukoencephalopathy With Subcortical Cysts AR 604004
Megalencephalic Leukoencephalopathy With Subcortical Cysts 2A AR 613925
Megalencephalic Leukoencephalopathy With Subcortical Cysts 2B, Remitting, With Or Without Mental Retardation AD 613926
Megalencephaly-Capillary Malformation-Polymicrogyria syndrome, Somatic 602501
Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome 1 AD 603387
Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome 2 AD 615937
Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome 3 AD 615938
Mental Retardation With Language Impairment And Autistic Features AD 613670
Mental Retardation, Autosomal Dominant 18 AD 615074
Mental retardation, autosomal dominant 35 AD 616355
Mental Retardation, Autosomal Dominant 49 AD 617752
Mental retardation, autosomal recessive 41 AR 615637
Mental Retardation, X-Linked 72 XL 300271
Mental Retardation, X-Linked 93 XL 300659
Mental retardation, X-linked syndromic, Turner type XL 309590
Mental Retardation, X-Linked, Syndromic 14 XL 300676
Mental Retardation, X-Linked, With Short Stature, Hypogonadism, And Abnormal Gait XL 300354
Muenke Syndrome AD 602849
Neurocutaneous melanosis, somatic 249400
Neurodevelopmental disorder with alopecia and brain abnormalities AD 619075
Neurofibromatosis, Familial Spinal AD 162210
Neurofibromatosis, Type 1 AD 162200
Neurofibromatosis-Noonan Syndrome AD 601321
Noonan Syndrome 3 AD 609942
Noonan Syndrome 4 AD 610733
Noonan Syndrome 6 AD 613224
Noonan syndrome-like disorder with loose anagen hair 2 AD 617506
O'Donnell-Luria-Rodan syndrome AD 618512
Oculoectodermal syndrome, somatic 600268
OHDO Syndrome, X-linked; OHDOX XL 300895
Oral-Facial-Digital Syndrome XL 311200
Pallister-Hall Syndrome AD 146510
Pancreatic Cancer 260350
Pelger-Huet Anomaly AD 169400
Pelger-Huet anomaly with mild skeletal anomalies 618019
Perlman Syndrome AR 267000
Phelan-Mcdermid Syndrome AD 606232
Pleuropulmonary Blastoma AD 601200
Polydactyly Preaxial Type 4 AD 174700
Polydactyly, Postaxial, Type A1 AD 174200
Polyhydramnios, Megalencephaly, And Symptomatic Epilepsy AR 611087
Premature aging syndrome, Penttinen type AD 601812
Primrose Syndrome AD 259050
Rahman syndrome AD 617537
RAS-Associated Autoimmune Leukoproliferative Disorder 614470
Reynolds Syndrome AD 613471
Rhabdomyosarcoma, embryonal, 2 180295
Robinow Syndrome AD 180700
Robinow syndrome, autosomal dominant 2 AD 616331
SADDAN AD 616482
Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic 163200
Schizophrenia 15 AD 613950
Sclerosteosis AR 269500
Shashi-Pena syndrome AD 617190
Simpson-Golabi-Behmel Syndrome XL 312870
Simpson-Golabi-Behmel Syndrome, Type 2 XL 300209
Smith-Kingsmore Syndrome AD 616638
Snijders Blok-Campeau syndrome AD 618205
Sotos Syndrome 2 AD 614753
Sotos' Syndrome AD 117550
Spitz nevus or nevus spilus, somatic 137550
Spongy Degeneration Of Central Nervous System AR 271900
Stiff Skin Syndrome AD 184900
Tatton-Brown-Rahman Syndrome AD 615879
Temple-Baraitser Syndrome AD 611816
Tenorio Syndrome AD 616260
Testicular Cancer 273300
Thanatophoric Dysplasia Type 1 AD 187600
Thanatophoric Dysplasia Type 2 AD 187601
Thauvin-Robinet-Faivre syndrome AR 617107
Thyroid Cancer, Follicular 188470
Vacterl Association With Hydrocephalus AR 276950
Waisman Syndrome XL 311510
Watson Syndrome AD 193520
Weaver Syndrome AD 277590
Weill-Marchesani Syndrome 2 AD 608328
Zimmermann-Laband Syndrome 1 AD 135500

Related Test

Name
PGxome®

Citations

  • Human Gene Mutation Database (Biobase).
  • Marsh et al. 1998. PubMed ID: 9467011
  • Mester and Eng. 2013. PubMed ID: 23613428
  • Neylon et al. 2012. PubMed ID: 22705997
  • Olney. 2007. PubMed ID: 17980309
  • Saugier-Veber et al. 2007. PubMed ID: 17565729
  • Shuman et al. 2016. PubMed ID: 20301568
  • Tatton-Brown et al. 2011. PubMed ID: 22190405
  • Verge and Mowat. 2010. PubMed ID: 20371592

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


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