Overgrowth and Macrocephaly Syndromes Panel

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).

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.

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).

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. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).