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Identification and functional characterization of novel monogenic causes for spina bifida

Subject Area Pediatric and Adolescent Medicine
Human Genetics
Term from 2022 to 2025
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 499462148
 
Final Report Year 2024

Final Report Abstract

Congenital anomalies occur in around 3-6% of all newborns and constitute one of the main causes of neonatal mortality. The most common malformations include congenital anomalies of the kidney and urinary tract (CAKUT), neural tube and abdominal wall defects. Many studies have shown the influence of genetic causes on the development of these defects. The aim of my research was therefore to identify potential new candidate genes for these malformations and to characterize them functionally. Exome sequencing (ES) data from 731 families with CAKUT was analysed to identify new candidate genes. A variant in a potentially new CAKUT gene was found in 19.43% of the families. In one of these families an early homozygous nonsense variant was identified in ETV4, which leads to a total loss of the protein. In the literature, there is so far only one CAKUT family with a biallelic variant in ETV4, for which pathogenicity has been demonstrated. The discovery of a second family with isolated CAKUT and a homozygous variant in ETV4 confirms the involvement of ETV4 in monogenic autosomal recessive CAKUT. Further analysis of 229 trio families allowed the identification of de novo variants in 45 new candidate genes, accounting for 17.90% of the families. A prioritization method was developed, which identified de novo variants in SOX13 and PROX1 as most promising novel causes of CAKUT. Functional studies indicated loss of function for the identified SOX13 and several PROX1 mutants compared to the wild type. These findings suggest that de novo variants play an important role in the development of CAKUT, and we here propose SOX13 and PROX1 as promising candidate genes for CAKUT. ES also identified additional individuals affected by neural tube defects and/or CAKUT who carried variants in the candidate gene MTMR8. The discovery of further allele carriers strengthens MTMR8 as a candidate gene, indicating MTMR8’s involvement in the pathogenesis of both diseases. Furthermore, we here identified ABL1 as the first candidate gene for familial isolated omphalocele, a condition characterized by a herniation of abdominal organs. Through ES analysis, a splice variant in ABL1 was discovered, leading to alternative splicing and a premature stop codon. This splice variant showed a different subcellular localization and expression pattern compared to the wild type, indicating a loss of function. Expression studies in murine embryos revealed that Abl1 is expressed during the time of abdominal wall closure in the umbilical cord. These molecular and experimental findings suggest that ABL1 plays a role in the development of omphalocele. The research data I have obtained improves our understanding of embryonic development and pathomechanisms of congenital malformations. In addition, the knowledge of a molecular genetic diagnosis enables personalized genetic counselling, optimized clinical care, future family planning and research into future therapeutic options.

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