Paediatric disorders: genes and variants

Genes linked to Paediatric disorders

• CHD8: ATP-dependent chromatin remodeler CHD8

  It remodels chromatin at neurodevelopmental and cell-cycle regulatory genes and influences expression of many autism-associated pathways. Haploinsufficiency causes a neurodevelopmental syndrome frequently marked by autism-related features, developmental delay, and macrocephaly.

  1 disease-causing and 16 uncertain variants in CHD8 are linked to Paediatric disorders.

• ALPL: Alkaline phosphatase, tissue-nonspecific isozyme

  It hydrolyzes extracellular pyrophosphate and other phosphate-containing substrates, enabling normal mineralization of bone and teeth. Loss-of-function variants cause hypophosphatasia, with severity ranging from lethal perinatal skeletal hypomineralization to adult fractures and dental disease.

  1 disease-causing and 0 uncertain variants in ALPL are linked to Paediatric disorders.

• COL2A1: Collagen alpha-1(II) chain

  It provides the principal fibrillar collagen framework of cartilage and is also important in the vitreous and inner ear. Pathogenic variants cause a broad type II collagenopathy spectrum including Stickler syndrome, spondyloepiphyseal dysplasia, and severe skeletal dysplasias.

  1 disease-causing and 0 uncertain variants in COL2A1 are linked to Paediatric disorders.

• DNMT3A: DNA (cytosine-5)-methyltransferase 3A

  It establishes new DNA methylation patterns during development and hematopoietic differentiation. Somatic variants are common in clonal hematopoiesis and acute myeloid leukemia, while germline variants cause Tatton-Brown-Rahman overgrowth syndrome.

  1 disease-causing and 0 uncertain variants in DNMT3A are linked to Paediatric disorders.

• HRAS: GTPase HRas

  Its GTP-bound state activates RAF-MEK-ERK and other pathways downstream of growth-factor receptors. Somatic activating variants drive several cancers, while germline activating variants cause Costello syndrome.

  1 disease-causing and 0 uncertain variants in HRAS are linked to Paediatric disorders.

• KCNQ2: Potassium voltage-gated channel subfamily KQT member 2

  Together with KCNQ3, its slowly activating potassium current provides much of the neuronal M-current that suppresses repetitive firing. Pathogenic variants cause a spectrum from self-limited familial neonatal epilepsy to severe developmental and epileptic encephalopathy.

  1 disease-causing and 0 uncertain variants in KCNQ2 are linked to Paediatric disorders.

Weakly linked (only a few uncertain records): ACTC1, HCN1 and WWOX.

Known disease-causing variants in Paediatric disorders

Same protein, different disease

• Intellectual developmental disorder with autism and macrocephaly is also caused by CHD8 variants; they fall mostly in different places as the Paediatric disorders variants (10 disease-causing).
• Hypophosphatasia is also caused by ALPL variants; they fall mostly in different places as the Paediatric disorders variants (172 disease-causing).
• Adult hypophosphatasia is also caused by ALPL variants; they fall mostly in different places as the Paediatric disorders variants (113 disease-causing).
• Childhood hypophosphatasia is also caused by ALPL variants; they fall mostly in different places as the Paediatric disorders variants (60 disease-causing).
• Infantile hypophosphatasia is also caused by ALPL variants; they fall mostly in different places as the Paediatric disorders variants (40 disease-causing).
• Hypophosphataemia or rickets is also caused by ALPL variants; they fall mostly in different places as the Paediatric disorders variants (8 disease-causing).
• Spondyloepiphyseal dysplasia congenita is also caused by COL2A1 variants; they fall mostly in different places as the Paediatric disorders variants (38 disease-causing).
• Achondrogenesis type II is also caused by COL2A1 variants; they fall mostly in different places as the Paediatric disorders variants (34 disease-causing).
• Stickler syndrome is also caused by COL2A1 variants; they fall mostly in different places as the Paediatric disorders variants (26 disease-causing).
• Spondyloepimetaphyseal dysplasia, Strudwick type is also caused by COL2A1 variants; they fall mostly in different places as the Paediatric disorders variants (18 disease-causing).
• Connective tissue disorder is also caused by COL2A1 variants; they fall mostly in different places as the Paediatric disorders variants (15 disease-causing).
• Tatton-Brown-Rahman overgrowth syndrome is also caused by DNMT3A variants; they fall mostly in different places as the Paediatric disorders variants (32 disease-causing).
• Heyn-Sproul-Jackson syndrome is also caused by DNMT3A variants; they fall mostly in different places as the Paediatric disorders variants (5 disease-causing).
• Acute myeloid leukemia is also caused by DNMT3A variants; they fall mostly in different places as the Paediatric disorders variants (5 disease-causing).
• Costello syndrome is also caused by HRAS variants; they fall mostly in different places as the Paediatric disorders variants (15 disease-causing).
• RASopathy is also caused by HRAS variants; they fall partly in the same places as the Paediatric disorders variants (6 disease-causing).
• Large congenital melanocytic nevus is also caused by HRAS variants; they fall partly in the same places as the Paediatric disorders variants (5 disease-causing).
• Epidermal nevus is also caused by HRAS variants; they fall mostly in different places as the Paediatric disorders variants (3 disease-causing).
• Thyroid cancer, nonmedullary, 2 is also caused by HRAS variants; they fall mostly in different places as the Paediatric disorders variants (3 disease-causing).
• Early-infantile DEE is also caused by KCNQ2 variants; they fall mostly in different places as the Paediatric disorders variants (199 disease-causing).
• Seizures, benign familial neonatal, 1 is also caused by KCNQ2 variants; they fall mostly in different places as the Paediatric disorders variants (57 disease-causing).

Diseases related to Paediatric disorders

• Early-infantile DEE, also linked to KCNQ2
• Osteogenesis imperfecta, also linked to ALPL
• Hypertrophic cardiomyopathy, also linked to HRAS
• RASopathy, also linked to HRAS
• Hypophosphatasia, also linked to ALPL
• Noonan syndrome, also linked to HRAS
• Adult hypophosphatasia, also linked to ALPL
• Noonan syndrome and Noonan-related syndrome, also linked to HRAS
• Seizures, benign familial neonatal, 1, also linked to KCNQ2
• Childhood hypophosphatasia, also linked to ALPL
• Infantile hypophosphatasia, also linked to ALPL
• Complex neurodevelopmental disorder, also linked to CHD8

Frequently asked questions

Which genes are linked to Paediatric disorders?

In CATVariant, Paediatric disorders is linked to 6 analyzed proteins: CHD8 (ATP-dependent chromatin remodeler CHD8), ALPL (Alkaline phosphatase, tissue-nonspecific isozyme), COL2A1 (Collagen alpha-1(II) chain), DNMT3A (DNA (cytosine-5)-methyltransferase 3A), HRAS (GTPase HRas) and KCNQ2 (Potassium voltage-gated channel subfamily KQT member 2).

How many genetic variants are linked to Paediatric disorders?

25 variants: 6 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 19 are of uncertain significance or have conflicting reports.

Which uncertain variants in Paediatric disorders look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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