<abstract xmlns="http://www.w3.org/1999/xhtml"><p>Kabuki syndrome (KS) is characterized by typical facial features and patients are also affected by multiple congenital anomalies, of which congenital heart anomalies (CHAs) are present in 28.0 to 80.0%. In approximately 75.0% of patients, the genetic causes of KS are caused by mutation in the <italic>KMT2D</italic> gene. Although KS is a well-characterized syndrome, reaching the diagnosis in neonates is still challenging. Namely, newborns usually display mild facial features; therefore the diagnosis is mainly based on congenital malformations. In our case, a newborn was referred for next generation sequencing (NGS) testing due to the prenatally observed CHA. After birth, a ventricular septal defect (VSD), vesicoureteral reflux, muscular hypotonia, cleft palate, mild microcephaly, and some dysmorphic features, were noted. The NGS analysis was performed on the proband’s genomic DNA using the TruSight One Sequencing Panel, which enriches exons of 4813 genes with clinical relevance to the disease. After variant calling, NGS data analysis was predominantly focused on rare variants in genes involved in VSD, microcephaly, and muscular hypotonia; features observed predominantly in our proband. With the aforementioned protocol, we were able to determine the previously unreported <italic>de novo</italic> frameshift deletion in the <italic>KMT2D</italic> gene resulting in translation termination. Although our proband is a typical representative of KS, his diagnosis was reached only after NGS analysis. Our proband thus represents the importance of genotypephenotype driven NGS analysis in diagnosis of patients with congenital anomalies.</p></abstract>

Kabuki syndrome (KS) is characterized by typical facial features and patients are also affected by multiple congenital anomalies, of which congenital heart anomalies (CHAs) are present in 28.0 to 80.0%. In approximately 75.0% of patients, the genetic causes of KS are caused by mutation in the KMT2D gene. Although KS is a well-characterized syndrome, reaching the diagnosis in neonates is still challenging. Namely, newborns usually display mild facial features; therefore the diagnosis is mainly based on congenital malformations. In our case, a newborn was referred for next generation sequencing (NGS) testing due to the prenatally observed CHA. After birth, a ventricular septal defect (VSD), vesicoureteral reflux, muscular hypotonia, cleft palate, mild microcephaly, and some dysmorphic features, were noted. The NGS analysis was performed on the proband’s genomic DNA using the TruSight One Sequencing Panel, which enriches exons of 4813 genes with clinical relevance to the disease. After variant calling, NGS data analysis was predominantly focused on rare variants in genes involved in VSD, microcephaly, and muscular hypotonia; features observed predominantly in our proband. With the aforementioned protocol, we were able to determine the previously unreported de novo frameshift deletion in the KMT2D gene resulting in translation termination. Although our proband is a typical representative of KS, his diagnosis was reached only after NGS analysis. Our proband thus represents the importance of genotypephenotype driven NGS analysis in diagnosis of patients with congenital anomalies.

<italic>De novo KMT2D</italic> heterozygous frameshift deletion in a newborn with a congenital heart anomaly

Balkan Journal of Medical Genetics

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

 heterozygous frameshift deletion in a newborn with a congenital heart anomaly

Kabuki syndrome (KS) is characterized by typical facial features and patients are also affected by multiple congenital anomalies, of which congenital heart...

De novo KMT2D heterozygous frameshift deletion in a newborn with a congenital heart anomaly

Article Category: Case Report

Published Online: Aug 26, 2020

Page range: 83 - 90

DOI: https://doi.org/10.2478/bjmg-2020-0008

Keywords
Congenital heart anomalies (CHAs), Genetics, gene, Kabuki syndrome (KS), Next generation sequencing (NGS) analysis

© 2020 Stangler Herodež Š, Marčun Varda N, Kokalj Vokač N, Krgović D, published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

De novo KMT2D heterozygous frameshift deletion in a newborn with a congenital heart anomaly

Article Category: Case Report

Published Online: Aug 26, 2020

Page range: 83 - 90

DOI: https://doi.org/10.2478/bjmg-2020-0008

KeywordsCongenital heart anomalies (CHAs), Genetics, gene, Kabuki syndrome (KS), Next generation sequencing (NGS) analysis

© 2020 Stangler Herodež Š, Marčun Varda N, Kokalj Vokač N, Krgović D, published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Keywords
Congenital heart anomalies (CHAs), Genetics, gene, Kabuki syndrome (KS), Next generation sequencing (NGS) analysis