Fetal anomalies with a likely genetic cause: genes and variants

Genes linked to Fetal anomalies with a likely genetic cause

• 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.

  2 disease-causing and 1 uncertain variants in COL2A1 are linked to Fetal anomalies with a likely genetic cause.

• CDC42: Cell division control protein 42 homolog

  It acts as a molecular switch controlling actin organization, cell polarity, migration, vesicle trafficking, and multiple developmental signaling pathways. Germline dysregulating variants can cause Takenouchi-Kosaki syndrome and related neurodevelopmental disorders with hematologic and immune abnormalities.

  1 disease-causing and 0 uncertain variants in CDC42 are linked to Fetal anomalies with a likely genetic cause.

• COL1A1: Collagen alpha-1(I) chain

  The alpha-1 chain of type I collagen, the main fibrillar collagen in connective tissue, bone, and skin. Together with its partner chain, it forms strong extracellular fibers, and COL1A1 variants are associated with osteogenesis imperfecta and several Ehlers-Danlos syndromes.

  1 disease-causing and 0 uncertain variants in COL1A1 are linked to Fetal anomalies with a likely genetic cause.

• COL6A3: Collagen alpha-3(VI) chain

  It forms part of collagen VI microfibrils that organize the extracellular matrix around muscle fibers and many other cells. Pathogenic variants can cause Bethlem or Ullrich-spectrum collagen VI myopathy and, in some alleles, isolated dystonia.

  1 disease-causing and 0 uncertain variants in COL6A3 are linked to Fetal anomalies with a likely genetic cause.

• GALT: Galactose-1-phosphate uridylyltransferase

  It converts galactose-1-phosphate and UDP-glucose into glucose-1-phosphate and UDP-galactose in the Leloir pathway. Biallelic deficiency causes classic galactosemia, in which dietary galactose can lead to neonatal liver failure, sepsis risk, cataracts, and long-term complications.

  1 disease-causing and 0 uncertain variants in GALT are linked to Fetal anomalies with a likely genetic cause.

• ITGB4: Integrin beta-4

  It pairs with alpha6 integrin in hemidesmosomes to anchor epithelial cells to laminin-rich basement membranes. Biallelic loss-of-function variants can cause junctional epidermolysis bullosa with pyloric atresia and severe epithelial fragility.

  1 disease-causing and 0 uncertain variants in ITGB4 are linked to Fetal anomalies with a likely genetic cause.

• KRAS: GTPase KRas

  A small GTPase that acts as a molecular switch in the RAS-MAPK signaling pathway. By cycling between GDP- and GTP-bound states, it relays growth and survival signals, and activating KRAS variants are common drivers of cancer.

  1 disease-causing and 0 uncertain variants in KRAS are linked to Fetal anomalies with a likely genetic cause.

• ORC1: Origin recognition complex subunit 1

  It helps mark replication origins and assemble the prereplication complex needed to license DNA replication once per cell cycle. Biallelic pathogenic variants cause Meier-Gorlin syndrome, characterized by severe growth restriction, microtia, and absent or small patellae.

  1 disease-causing and 0 uncertain variants in ORC1 are linked to Fetal anomalies with a likely genetic cause.

• SOX9: Transcription factor SOX-9

  It controls chondrocyte differentiation, cartilage formation, and testis development and also regulates multiple organ-specific developmental programs. Haploinsufficiency causes campomelic dysplasia, often with severe skeletal abnormalities and 46,XY sex reversal.

  1 disease-causing and 0 uncertain variants in SOX9 are linked to Fetal anomalies with a likely genetic cause.

• TREX1: Three-prime repair exonuclease 1

  It degrades aberrant cytosolic DNA and prevents inappropriate activation of the cGAS-STING interferon pathway. Pathogenic variants cause interferon-mediated diseases including Aicardi-Goutieres syndrome and familial chilblain lupus, and certain alleles cause retinal vasculopathy with cerebral leukoencephalopathy.

  1 disease-causing and 0 uncertain variants in TREX1 are linked to Fetal anomalies with a likely genetic cause.

Weakly linked (only a few uncertain records): ALPL, NF1, PIEZO1, TUBA1A and UNC13D.

Known disease-causing variants in Fetal anomalies with a likely genetic cause

Which prediction tools work for Fetal anomalies with a likely genetic cause

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• CATVariant: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 90 out of 100
• PolyPhen-2: 86 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Spondyloepiphyseal dysplasia congenita is also caused by COL2A1 variants; they fall mostly in different places as the Fetal anomalies with a likely genetic cause variants (38 disease-causing).
• Achondrogenesis type II is also caused by COL2A1 variants; they fall mostly in different places as the Fetal anomalies with a likely genetic cause variants (34 disease-causing).
• Stickler syndrome is also caused by COL2A1 variants; they fall mostly in different places as the Fetal anomalies with a likely genetic cause variants (26 disease-causing).
• Spondyloepimetaphyseal dysplasia, Strudwick type is also caused by COL2A1 variants; they fall mostly in different places as the Fetal anomalies with a likely genetic cause variants (18 disease-causing).
• Connective tissue disorder is also caused by COL2A1 variants; they fall mostly in different places as the Fetal anomalies with a likely genetic cause variants (15 disease-causing).
• Macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome is also caused by CDC42 variants; they fall mostly in different places as the Fetal anomalies with a likely genetic cause variants (6 disease-causing).
• Osteogenesis imperfecta is also caused by COL1A1 variants; they fall mostly in different places as the Fetal anomalies with a likely genetic cause variants (239 disease-causing).
• Osteogenesis imperfecta, perinatal lethal is also caused by COL1A1 variants; they fall mostly in different places as the Fetal anomalies with a likely genetic cause variants (52 disease-causing).
• Osteogenesis imperfecta with normal sclerae, dominant form is also caused by COL1A1 variants; they fall mostly in different places as the Fetal anomalies with a likely genetic cause variants (34 disease-causing).
• Infantile cortical hyperostosis is also caused by COL1A1 variants; they fall mostly in different places as the Fetal anomalies with a likely genetic cause variants (15 disease-causing).
• Ehlers-Danlos syndrome, arthrochalasia type is also caused by COL1A1 variants; they fall mostly in different places as the Fetal anomalies with a likely genetic cause variants (10 disease-causing).
• Bethlem myopathy is also caused by COL6A3 variants; they fall mostly in different places as the Fetal anomalies with a likely genetic cause variants (21 disease-causing).
• Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase is also caused by GALT variants; they fall mostly in different places as the Fetal anomalies with a likely genetic cause variants (65 disease-causing).
• Galactosemia is also caused by GALT variants; they fall mostly in different places as the Fetal anomalies with a likely genetic cause variants (36 disease-causing).
• Junctional epidermolysis bullosa with pyloric atresia is also caused by ITGB4 variants; they fall mostly in different places as the Fetal anomalies with a likely genetic cause variants (13 disease-causing).
• Epidermolysis bullosa, junctional 5A, intermediate is also caused by ITGB4 variants; they fall mostly in different places as the Fetal anomalies with a likely genetic cause variants (5 disease-causing).

Diseases related to Fetal anomalies with a likely genetic cause

• Connective tissue disorder, also linked to COL1A1, COL2A1 and SOX9
• Osteogenesis imperfecta, also linked to COL1A1
• Ehlers-Danlos syndrome, classic type, 1, also linked to COL1A1
• RASopathy, also linked to KRAS
• Ehlers-Danlos syndrome, also linked to COL1A1
• Noonan syndrome, also linked to KRAS
• Bethlem myopathy, also linked to COL6A3
• Osteogenesis imperfecta, perinatal lethal, also linked to COL1A1
• Osteogenesis imperfecta with normal sclerae, dominant form, also linked to COL1A1
• Noonan syndrome and Noonan-related syndrome, also linked to KRAS
• Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase, also linked to GALT
• Cardiofaciocutaneous syndrome, also linked to KRAS

Frequently asked questions

Which genes are linked to Fetal anomalies with a likely genetic cause?

In CATVariant, Fetal anomalies with a likely genetic cause is linked to 10 analyzed proteins: COL2A1 (Collagen alpha-1(II) chain), CDC42 (Cell division control protein 42 homolog), COL1A1 (Collagen alpha-1(I) chain), COL6A3 (Collagen alpha-3(VI) chain), GALT (Galactose-1-phosphate uridylyltransferase), ITGB4 (Integrin beta-4) and 4 more.

How many genetic variants are linked to Fetal anomalies with a likely genetic cause?

17 variants: 11 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 6 are of uncertain significance or have conflicting reports.

Which uncertain variants in Fetal anomalies with a likely genetic cause look disease-causing?

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

Which variant effect predictor works best for Fetal anomalies with a likely genetic cause?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.90, based on 11 disease-causing and 630 harmless variants).

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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