Novel De Novo KAT6A Variant in a Pediatric Patient with Multisystem Involvement
Laboratory Genetics and Genomics
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Primary Categories:
- Laboratory Genetics
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Secondary Categories:
- Laboratory Genetics
Introduction
KAT6A-related syndromes are rare genetic disorders associated with a wide range of clinical manifestations, including intellectual disability, speech delay, microcephaly, cardiac anomalies, and gastrointestinal complications. We report a 15-year-old girl with a complex clinical presentation and a novel de novo KAT6A variant, including the unique finding of polysplenia, possible expanding the phenotypic spectrum.
Case Presentation
The patient presented with a history of multiple pneumo- and hemothoraces, chronic lung disease, pulmonary hypertension, polysplenia (at least three spleens), patent ductus arteriosus (PDA), global developmental delay, limited speech, and anxiety. Additional findings included esotropia, tall forehead, bitemporal narrowing, inverted nipples, abnormal palmar creases, hyperconvex nails, sacral dimple, and gastroesophageal reflux. Neuroimaging (EEG and MRI) revealed mild ventriculomegaly and mild prominence of extra-axial fluid spaces, with otherwise normal brain anatomy and intracranial arteries. The presence of polysplenia is a rare and previously unreported finding in KAT6A-related conditions, raising the possibility of phenotype expansion. Further studies are needed to clarify the relationship between polysplenia and KAT6A variants.
Diagnostic Workup
Initial genetic testing, including SNP microarray and Noonan syndrome sequencing panel, were negative. To explore potential pathogenic variants, trio-based genome sequencing was performed, revealing a novel de novo 5-bp deletion (c.5161_5165del) in the KAT6A gene (MIM: 601408). This variant, located in the final exon, is predicted to cause a frameshift and is likely to escape nonsense-mediated decay (NMD), potentially leading to a truncated protein.
Discussion
To explore the pathogenic consequences of this variant, a literature search identified several published cases of KAT6A-related conditions involving frameshift and nonsense mutations downstream of the variant we identified, further supporting the pathogenicity of C-terminal loss of function variants. In addition, the late-truncating variants in exons 16 and 17 are associated with phenotypes closely matching our patient. This case highlights the identification of a novel de novo KAT6A variant and provides an opportunity to explore a possible association between KAT6A variants and polysplenia, a rare condition that has not yet been documented in the context of KAT6A-related disorders.
Conclusion
The patient's complex clinical presentation aligns with features of KAT6A-related syndromes, emphasizing the diverse manifestations of this condition. This case underscores the utility of genome sequencing in diagnosing rare genetic disorders with overlapping phenotypes, particularly when conventional testing yields negative results. Finally, further research is needed to fully understand the role of polysplenia in KAT6A-related disorders.
KAT6A-related syndromes are rare genetic disorders associated with a wide range of clinical manifestations, including intellectual disability, speech delay, microcephaly, cardiac anomalies, and gastrointestinal complications. We report a 15-year-old girl with a complex clinical presentation and a novel de novo KAT6A variant, including the unique finding of polysplenia, possible expanding the phenotypic spectrum.
Case Presentation
The patient presented with a history of multiple pneumo- and hemothoraces, chronic lung disease, pulmonary hypertension, polysplenia (at least three spleens), patent ductus arteriosus (PDA), global developmental delay, limited speech, and anxiety. Additional findings included esotropia, tall forehead, bitemporal narrowing, inverted nipples, abnormal palmar creases, hyperconvex nails, sacral dimple, and gastroesophageal reflux. Neuroimaging (EEG and MRI) revealed mild ventriculomegaly and mild prominence of extra-axial fluid spaces, with otherwise normal brain anatomy and intracranial arteries. The presence of polysplenia is a rare and previously unreported finding in KAT6A-related conditions, raising the possibility of phenotype expansion. Further studies are needed to clarify the relationship between polysplenia and KAT6A variants.
Diagnostic Workup
Initial genetic testing, including SNP microarray and Noonan syndrome sequencing panel, were negative. To explore potential pathogenic variants, trio-based genome sequencing was performed, revealing a novel de novo 5-bp deletion (c.5161_5165del) in the KAT6A gene (MIM: 601408). This variant, located in the final exon, is predicted to cause a frameshift and is likely to escape nonsense-mediated decay (NMD), potentially leading to a truncated protein.
Discussion
To explore the pathogenic consequences of this variant, a literature search identified several published cases of KAT6A-related conditions involving frameshift and nonsense mutations downstream of the variant we identified, further supporting the pathogenicity of C-terminal loss of function variants. In addition, the late-truncating variants in exons 16 and 17 are associated with phenotypes closely matching our patient. This case highlights the identification of a novel de novo KAT6A variant and provides an opportunity to explore a possible association between KAT6A variants and polysplenia, a rare condition that has not yet been documented in the context of KAT6A-related disorders.
Conclusion
The patient's complex clinical presentation aligns with features of KAT6A-related syndromes, emphasizing the diverse manifestations of this condition. This case underscores the utility of genome sequencing in diagnosing rare genetic disorders with overlapping phenotypes, particularly when conventional testing yields negative results. Finally, further research is needed to fully understand the role of polysplenia in KAT6A-related disorders.