Five Variations in HSF4 Causing Congenital Cataract

Congenital cataract represents a significant cause of visual impairment in children worldwide, often rooted in genetic mutations. Among these, variants in the HSF4 gene, encoding heat shock transcription factor 4, are recognized for their role in hereditary cataracts. In this article, we explores five notable HSF4 mutations identified in probands/families affected by congenital cataracts, highlighting how these findings deepen our understanding of cataract etiology and the importance of comprehensive variant databases. The association is found to be definitive/strong from genecc submitters.

1. Missense Mutation in HSF4 Causing Autosomal-Dominant Lamellar Cataract

• Mutation: HSF4:c.190A>G (p.Lys64Glu)
• Summary: Identified in a five-generation British family, this mutation lies within the DNA-binding domain of HSF4 and is believed to disrupt DNA-binding affinity. This novel mutation is autosomal dominant and adds to the catalog of British HSF4-associated cataract cases.
• ClinVar Status: Variant is present but not associated with the article.
• PMID: 29243736

2. Recessive Cataract Linked to a Homozygous Mutation in HSF4

• Mutation: HSF4:c.521T>C (p.Leu174Pro)
• Summary: In an Iranian consanguineous family, two siblings with autosomal recessive congenital cataract were identified with this mutation, located in a hydrophobic repeat of the HSF4 protein. This placement aligns with the recessive inheritance pattern of the mutation.
• ClinVar Status: Absent
• PMID: 26490182

3. HSF4 Mutation in a Chinese Family with Cataract

• Mutation: HSF4:c.331C>T [Not mapped to any HSF4 transcripts]
• Summary: A Chinese family presented with an autosomal dominant form of congenital cataract associated with a HSF4 mutation. This substitution in exon 3 led to a change from arginine to cysteine at position 111, segregating with the disease.
• PMID: 25877371

4. Nonsense Mutation Causing Autosomal Recessive Cataracts in a Pakistani Family

• Mutation: HSF4:c.1213C>T (p.Arg405Ter)
• Summary: This first nonsense mutation in HSF4 was discovered in a large consanguineous Pakistani family with autosomal recessive cataracts, supporting the growing evidence of HSF4’s role in various cataract phenotypes.
• ClinVar Status: Present, further evidence required for full characterization.
• PMID: 19014451

5. Conflicting Variant Reports in a Chinese Family with Total White Cataract

• Mutation: HSF4:c.221G>A (p.Arg74His) (Article) / HSF4:c.217C>T (p.Arg73Cys) (ClinVar)
• Summary: The study identified a mutation in a Chinese family causing congenital total white cataract. However, there’s inconsistency between the mutation reported in the article and the one recorded in ClinVar, underlining the necessity for rigorous data validation in variant interpretation.
• ClinVar Status: Conflicting variant identity.
• PMID: 16876512

6. Autosomal-Dominant Cataract in a Chinese Family

• Variant: HSF4:c.69G>T (p.Lys23Asn)
• Details: Missense mutation in HSF4 was identified in a Chinese family with congenital cataracts. Bioinformatics tools predict the mutation to be disease-causing, co-segregating with affected family members.
• ClinVar Status: Present.
• PMID: 24637349