Abstract: TH-PO467
Novel Double-Dominant Mutations of COL4A4 Gene Causing Alport Syndrome in a Hispanic Family
Session Information
- Genetic Diseases: Glomerulopathies - I
November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Hamed, Basant, SUNY The State University of New York, Brooklyn, New York, United States
- Rijal, Shikha, SUNY The State University of New York, Brooklyn, New York, United States
- Sriram, Aarthi, SUNY The State University of New York, Brooklyn, New York, United States
- Mongia, Anil K., SUNY The State University of New York, Brooklyn, New York, United States
Introduction
Autosomal recessive (AR) and Autosomal dominant (AD) disease account for 10-15% and 20-30% respectively of patients with Alport syndrome due to genetic defects in either the COL4A3 or COL4A4 genes. Here we report family of four patients with microscopic hematuria and proteinuria caused by 2 novel mutations of COL4A4 gene.
Case Description
We present a 13-year-old male patient who was presented with microscopic hematuria and proteinuria since the age of 4. Patient had normal audiology and ophthalmologic examination and normal renal function including serum creatinine. His brother, mother, and father had microscopic hematuria but no other symptoms. Genetic testing was performed for all four individuals using Next Generation Sequencing (NGS, Illumina) and confirmed COL4A4 gene mutation with 2 novel variants that is predicted to disrupt the canonical splice acceptor site for exon 9 and 29. The first intronic variant, NM_000092.5:c.559-2A>T, is predicted to abolish canonical splice acceptor activity while the second intronic variant, NM_000092.4:c.2545+2T>G, alters the highly conserved splice donor site for exon 29 and is predicted by all four splice site prediction tools queried to abolish canonical splice donor activity. Both variants are expected to result in altered function of the COL4A4 gene product as a result of aberrant splicing. Of these mutations, our patient has bi-paternally inherited variants with compound heterozygosity, while the rest of his family showed only one pathogenic variant, which can explain the severity of his microscopic hematuria and proteinuria.
Discussion
Here we report unusual double dominant inheritance pattern in a 13 year old boy who has inherited defective genes from both affected parents. These type of patients may have worst prognosis than other forms of Alport syndrome. Current classification needs to be revised in view of newer genetic information.
Clinical features and genetic findings in a family with Alport syndrome
| Subject | I (index case) | II (brother) | III (father) | IV (mother) |
| Sex | M | M | M | F |
| Age | 13 | 23 | 54 | 52 |
| Genotype | Heterozygous | Heterozygous | Heterozygous | Heterozygous |
| Variants | c.559-2A>T (p.?) c.2545+2T>G (p.?) | c.2545+2T>G (p.?) | c.2545+2T>G (p.?) | c.559-2A>T (p.?) |
| Classification | Likely pathogenic | Likely pathogenic | Likely pathogenic | Likely pathogenic |
| Microscopic hematuria | 3+ | 1+ | 1+ | 1+ |
| Urine protein/creatinine ratio | 1.4 | <0.2 | <0.2 | <0.2 |