Pathogenic variant in DACH1 may cause a new neurodevelopmental syndrome with hearing loss and nephropathy
Clinical Genetics and Therapeutics
-
Primary Categories:
- Clinical- Pediatric
-
Secondary Categories:
- Clinical- Pediatric
Introduction:
DACH1 is involvement in the EYA-SIX-DACH network of renal developmental genes. Branchio-Oto-Renal syndrome 1 (BOR1) is caused by pathogenic variants in EYA1. BOR2 is caused by pathogenic variants in SIX5. Schild et al. (2013) reported a patient with renal dysplasia carrying homozygous missense variants in both BMP4 and DACH1. Functional analyses of the identified DACH1 variant demonstrated enhanced suppression of the TGF-β pathway suggesting that both variants could act synergistically in the development of the phenotype. There is a growing body of evidence that the GATA and PAX-SIX-EYA-DACH transcriptional networks (PSEDNs) is crucial for normal development. We report a patient with a novel variant of DACH1.
Methods:
The patient underwent endotracheal intubation soon after birth due to congenital stridor. She underwent a tracheostomy after birth due to subglottic stenosis.
At the age of 4, she visited our medical center for evaluation of congenital hearing loss and psychomotor developmental delay. Routine laboratory investigations and microarray analysis yielded normal results. Several years later, she developed proteinuria, and nephropathy was diagnosed. She could not speak meaningful words. Facial features included down-slanted palpebral fissures, low set ears, and micrognathia.
Trio-based Whole-exome sequencing have been used for the genetic diagnoses of the patient. Genomic analysis of the patient was performed based on the Initiative on Rare and Undiagnosed Disease (IRUD) project in Japan to provide an accurate diagnosis, discover causes, and ultimately provide cures for rare and undiagnosed diseases.
Results:
A de novo heterozygous pathogenic variant DACH1 (p.Ser673Arg*fs5) was revealed. This variant is not registered in general databases and is considered pathogenic.
Conclusion:
The Dach1 gene is expressed in the inner ear of normal mouse embryos. Miwa et al. (2019) reported that inner ear-specific Dach1-KD mature mice showed hearing impairment and inner ear abnormality. DACH1 is expressed in kidney, where it is robustly expressed in the podocyte nucleus. Tanaka et al. (2024) reported that DACH1 is indispensable for maintaining the normal integrity of mature podocytes. These findings may potentially explain the hearing loss and renal dysfunction in this patient. Further research and accumulation of cases are required for this condition to be recognized as a novel syndrome.
DACH1 is involvement in the EYA-SIX-DACH network of renal developmental genes. Branchio-Oto-Renal syndrome 1 (BOR1) is caused by pathogenic variants in EYA1. BOR2 is caused by pathogenic variants in SIX5. Schild et al. (2013) reported a patient with renal dysplasia carrying homozygous missense variants in both BMP4 and DACH1. Functional analyses of the identified DACH1 variant demonstrated enhanced suppression of the TGF-β pathway suggesting that both variants could act synergistically in the development of the phenotype. There is a growing body of evidence that the GATA and PAX-SIX-EYA-DACH transcriptional networks (PSEDNs) is crucial for normal development. We report a patient with a novel variant of DACH1.
Methods:
The patient underwent endotracheal intubation soon after birth due to congenital stridor. She underwent a tracheostomy after birth due to subglottic stenosis.
At the age of 4, she visited our medical center for evaluation of congenital hearing loss and psychomotor developmental delay. Routine laboratory investigations and microarray analysis yielded normal results. Several years later, she developed proteinuria, and nephropathy was diagnosed. She could not speak meaningful words. Facial features included down-slanted palpebral fissures, low set ears, and micrognathia.
Trio-based Whole-exome sequencing have been used for the genetic diagnoses of the patient. Genomic analysis of the patient was performed based on the Initiative on Rare and Undiagnosed Disease (IRUD) project in Japan to provide an accurate diagnosis, discover causes, and ultimately provide cures for rare and undiagnosed diseases.
Results:
A de novo heterozygous pathogenic variant DACH1 (p.Ser673Arg*fs5) was revealed. This variant is not registered in general databases and is considered pathogenic.
Conclusion:
The Dach1 gene is expressed in the inner ear of normal mouse embryos. Miwa et al. (2019) reported that inner ear-specific Dach1-KD mature mice showed hearing impairment and inner ear abnormality. DACH1 is expressed in kidney, where it is robustly expressed in the podocyte nucleus. Tanaka et al. (2024) reported that DACH1 is indispensable for maintaining the normal integrity of mature podocytes. These findings may potentially explain the hearing loss and renal dysfunction in this patient. Further research and accumulation of cases are required for this condition to be recognized as a novel syndrome.