CoGenesis® Growth Disorders

CoGenesis® Growth Disorders is a targeted next-generation sequencing (NGS) panel covering 36 genes across the spectrum of rare hereditary growth disorders. It is designed to resolve the underlying genetic cause in patients with unexplained overgrowth, macrocephaly, or growth deficiency.

Growth is regulated by a complex interplay of hormonal signalling, epigenetic programming, and cellular proliferation pathways. Disruption of any of these systems can produce either excessive growth (overgrowth syndromes) developmental delay, or growth failure. Early genetic diagnosis may change clinical management.

Beckwith-Wiedemann spectrum (BWSp): The panel covers the major molecular causes of BWSp, including imprinting control region defects at 11p15.5 through H19, IGF2, and KCNQ1OT1 analysis, loss-of-function variants in CDKN1C, and GPC3 mutations causing Simpson-Golabi-Behmel syndrome — a BWSp-related condition with similar overgrowth and Wilms tumour risk. DIS3L2 mutations causing Perlman syndrome (foetal gigantism with Wilms tumour predisposition) are also included.

Epigenetic overgrowth syndromes: A cluster of chromatin-remodelling and histone-modifying genes are included, whose germline disruption causes syndromic overgrowth with intellectual disability. NSD1 (Sotos syndrome, the most common epigenetic overgrowth syndrome, ~1 in 14,000 births); EZH2 (Weaver syndrome); DNMT3A (Tatton-Brown-Rahman syndrome); EED (Cohen-Gibson syndrome); SUZ12 (Imagawa-Matsumoto syndrome); SETD2 (Luscan-Lumish syndrome); PPP2R5D (Jordan syndrome); HIST1H1E (Rahman syndrome); and ASXL2 (Shashi-Pena syndrome) are covered.

PI3K/AKT/mTOR pathway disorders: The panel covers major pathway genes responsible for generalised and segmental overgrowth, macrocephaly, and brain malformations: PIK3CA, AKT3, MTOR, AKT2, and PTEN.

IGF axis and growth deficiency: IGF1, IGF1R, IGF2, IGFBP1, and IGFBP3 are included to identify monogenic causes of growth hormone insensitivity, primordial dwarfism, and IGF-related growth failure. Additional genes covering syndromic overgrowth and macrocephaly include CHD8, HMGA2, PLAG1, NFIB, NFIX, HERC1, BRWD3, ABCC9, PDGFRB, OFD1, RNF125, and ZBTB7A.

Confirming a genetic diagnosis has clinical implications: patients with BWSp-associated genes require standardised tumour surveillance; PTEN mutation carriers need lifetime cancer surveillance; PIK3CA, AKT, and MTOR mutations may direct eligibility for mTOR inhibitor therapy (sirolimus) in segmental overgrowth syndromes.

1. Children with unexplained overgrowth (tall stature, macrosomia, macrocephaly) or neonatal features suggesting Beckwith-Wiedemann spectrum — including hemihyperplasia, exomphalos, neonatal hypoglycaemia, or Wilms tumour — in whom molecular subtyping will guide tumour surveillance protocols and recurrence risk counselling.

2. Patients with clinical features of a named epigenetic overgrowth syndrome (Sotos, Weaver, Tatton-Brown-Rahman, or related conditions) where initial single-gene testing or FISH/MLPA has been non-diagnostic and a broader panel approach is warranted.

3. Individuals with macrocephaly and autism spectrum disorder or intellectual disability requiring molecular evaluation of PI3K/AKT/mTOR pathway genes (PIK3CA, AKT3, MTOR, PTEN) to clarify diagnosis, define lifetime cancer risk, and assess potential eligibility for mTOR inhibitor therapy.

4. Children or adults with disproportionate short stature or growth failure unresponsive to standard growth hormone therapy in whom a primary defect in the IGF-1 signalling axis (IGF1, IGF1R, IGFBP3) is suspected, as the diagnosis determines eligibility for recombinant IGF-1 treatment.

5. Patients with segmental overgrowth, vascular or brain malformations (MCAP, MPPH, hemimegalencephaly) or asymmetric somatic overgrowth where a germline or mosaic PI3K/AKT/mTOR pathway variant is the suspected underlying mechanism.

2 sub-panels included:

4mL Peripheral blood (EDTA), 2mL saliva, or buccal swab

Preferred sample type:

• 4mL Blood (EDTA tube),
• Codex-provided buccal swabs (4 swabs)
• Codex-provided saliva collection kit (2mL)

Saliva or buccal swab sample collection: Follow the enclosed instructions; do not eat, drink, or smoke for 30 minutes before collection.

• Results may identify pathogenic, likely pathogenic, or variants of uncertain significance (VUS).
• Positive findings can inform risk‑reducing strategies and treatment options.
• Genetic counseling is recommended to help families understand implications.

Hereditary growth disorders encompass two broad phenotypic poles: 1) overgrowth syndromes characterised by above-average stature, macrocephaly, or somatic asymmetry; 2) growth-failure syndromes with short stature or IGF resistance.

Overgrowth syndromes as a group affect an estimated 1–2% of the paediatric genetics population, though individual conditions are rare. Beckwith-Wiedemann syndrome (BWS), the most common isolated overgrowth syndrome, affects approximately 1 in 10,500–13,700 births and results from epigenetic or genetic disruption of imprinted genes at chromosomal region 11p15.5 (H19, IGF2, KCNQ1OT1, CDKN1C). A critical feature is Wilms tumour predisposition (5–10% lifetime risk in some molecular subtypes), making molecular confirmation essential for risk stratification and surveillance planning. Simpson-Golabi-Behmel syndrome (GPC3) and Perlman syndrome (DIS3L2) carry Wilms tumour risks exceeding 10% and 60%, respectively, reinforcing the clinical urgency of molecular diagnosis.

Epigenetic overgrowth syndromes caused by germline mutations in chromatin-remodelling genes have emerged as a significant disease class. Sotos syndrome (NSD1), affecting ~1 in 14,000, is the best characterised, presenting with overgrowth, macrocephaly, and intellectual disability. Weaver syndrome (EZH2), Tatton-Brown-Rahman syndrome (DNMT3A), Cohen-Gibson syndrome (EED), and Luscan-Lumish syndrome (SETD2) form a growing cluster of overlapping disorders identifiable only through gene panel or exome sequencing. Pathogenic variants in EZH2, EED, and SUZ12 disrupt the Polycomb Repressive Complex 2, revealing a shared epigenetic mechanism underlying these seemingly distinct syndromes.

PI3K/AKT/mTOR pathway activation underlies brain overgrowth malformation syndromes. Megalencephaly-capillary malformation-polymicrogyria (MCAP; PIK3CA) and megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH; AKT3) cause severe macrocephaly with structural brain anomalies. PTEN hamartoma tumour syndrome, presenting in children as macrocephaly-autism syndrome, confers lifetime risks of breast, thyroid, and endometrial cancers requiring surveillance. Importantly, mTOR inhibitors (sirolimus) have demonstrated clinical benefit in PIK3CA-related overgrowth spectrum, making molecular diagnosis directly actionable.

The IGF-1 axis (IGF1, IGF1R, IGF2, IGFBP1, IGFBP3) mediates the downstream effects of growth hormone on linear growth. Monogenic defects cause primordial dwarfism and IGF deficiency or resistance. Distinguishing IGF-axis defects from GH receptor defects has direct therapeutic implications: recombinant IGF-1 (mecasermin) is specifically indicated for severe primary IGF deficiency where GH therapy is ineffective. CoGenesis® Growth Disorders may help delineate the clinical and molecular overlap between overgrowth and growth-failure syndromes and enabling efficient molecular diagnosis.