1. Unidade de Genética Médica, Área da Mulher, Criança e Adolescente, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
2. Serviço de Cardiologia Pediátrica, Hospital Santa Marta, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
3. CGC Genetics, Porto, Portugal
- 23.ª Reunião da Sociedade Portuguesa de Genética Humana, Coimbra, 14‑16 de novembro de 2019
Background: Germline variants in ABL1 gene were recently identified in six patients with the previously unreported congenital heart defects and skeletal malformations syndrome. It is an autosomal dominant disorder characterized by congenital atrial and ventricular septal defects, with aortic root dilation in adulthood; and variable skeletal defects such as pectus excavatum, scoliosis, and finger contractures.
Case report: Here, we report the case of a four-year-old girl referred to our clinic for multiple congenital anomalies, namely atrial and ventricular septal defects and pulmonary valve stenosis, bifid uvula, craniosynostosis, umbilical hernia, and finger contractures, resembling Loeys-Dietz syndrome, a hereditary connective tissue disorder (HCTD). At observation, it was noted borderline short stature and dysmorphic craniofacial features such as synophris, small nose, small deep-set eyes, micrognathia and microcephaly. Clinical exome sequencing revealed a pathogenic heterozygous variant in ABL1 gene, c.1066G>A (p.(Ala356Thr)). The A356T variant is not observed in large population cohorts, and it has been previously reported as a de novo variant in an individual with features of congenital heart defects and skeletal malformations syndrome. The A356T variant leads to an amino acid substitution, which is likely to impact secondary protein structure. Functional studies indicate that the A356T variant is associated with increased tyrosine phosphorylation. The literature review showed that clinical features were similar to all other patients with ABL variants; our case is the first presenting with craniosynostosis. Parental genetic testing is ongoing to confirm the de novo origin of the mutation.
Conclusion: This report further broadens the phenotypic spectrum of germline ABL1 variants associated syndrome, adding craniosynostosis as a further disease-associated feature. However, we cannot completely exclude the possibility of this feature not being related to the main diagnosis. We suggest clinical and genetic reassessment of other cases with overlapping features of HCTD since most next generation sequencing panels for HCTD often do not include the ABL1 gene.
Palavras Chave: congenital heart defects and skeletal malformations syndrome, ABL1 gene