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Next-generation sequencing reanalysis identifies Coffin-Siris syndrome with an initial diagnosis of hypertrophic cardiomyopathy

Open AccessPublished:September 19, 2022DOI:https://doi.org/10.1016/j.pedneo.2022.07.010
      Dear Editor
      Coffin-Siris syndrome (CSS) is a multiple congenital anomaly and/or intellectual disability syndrome that is characterized by fifth digit and/or nail hypoplasias, coarse facial features, and a range of organ-system-related anomalies. However, cardiac diseases are rarely the initial presentation of CSS.
      • Nemani L.
      • Barik R.
      • Patnaik AN
      • Mishra RC
      • Rao AM
      • Kapur P.
      Coffin-Siris syndrome with the rarest constellation of congenital cardiac defects: a case report with review of literature.
      Here, we report a newborn baby who was initially diagnosed with hypertrophic cardiomyopathy, but CSS diagnosis was only established by a reanalysis of whole exome sequencing (WES) at the age of 2 years after the appearance of autism (see Fig. 1).
      Figure 1
      Figure 1Clinical features of the patient. (a) Echocardiography which revealed cardiac hypertrophy and outflow tract obstruction. (b) Facial features of the patient.
      She was born at 40 weeks gestational age. Prenatal ultrasonography at 38 weeks reported dilated right atrium (RA) and right ventricle (RV). Unfortunately, hypothermia, respiratory distress, and poor activity were noted soon after birth. She was intubated with the use of assisted ventilatory support due to severe metabolic acidosis with a high lactic acid level (25.88 mmol/L). Echocardiography revealed dilated RA and RV, moderate tricuspid regurgitation, and pulmonary hypertension. Cardiac hypertrophy was found at 3 days of age, and propranolol was administered to abolish left and right ventricular outflow tract obstruction (LVOTO and RVOTO). Rapid trio WES revealed no hypertrophic cardiomyopathy-related disease.
      She gradually recovered, and LVOTO and RVOTO disappeared at 5 months of age. However, hypotonia and developmental delay were noted. A brain magnetic resonance imaging at 11 months of age revealed a diffusely thin body and splenium of the corpus callosum. She was diagnosed with autism at 2 years of age and was then referred to a geneticist, and facial dysmorphisms, including hypertelorism, broad nasal tip, low-set ears, and flat philtrum, were noted. A previous trio WES data reanalysis, with autism, served as one of the human phenotype ontology terms for variant prioritization and identified a de novo mutation c.4691del [p.(Pro1564LeufsTer13)] in ARID1B.
      Genes associated with CSS code for BAF chromatin remodeling complex components. The most frequently mutated gene in CSS is ARID1B, and the commonly associated phenotypes are mild-to-moderate intellectual disability, a facial gestalt reminiscent of CSS, hypertrichosis, and hypoplastic, and hardly ever absent fifth finger- and toenails. Cardiac anomalies, including ventricular septal defects, atrial septal defects, tetralogy of Fallot, and patent ductus arteriosus or patent foramen ovale, were occasionally reported. Hypertrophic cardiomyopathy was described in one patient with CSS
      • Alembik Y.
      • Roy E.
      • Hirsch E.
      • Tomb R.
      • Stoll C.
      Coffin-Siris syndrome with Lennox-Gastaut syndrome and hypertrophic cardiomyopathy. [Article in French].
      and a combination of biventricular outflow tract obstruction in another patient.
      • Nemani L.
      • Barik R.
      • Patnaik AN
      • Mishra RC
      • Rao AM
      • Kapur P.
      Coffin-Siris syndrome with the rarest constellation of congenital cardiac defects: a case report with review of literature.
      Currently, the cardiomyopathy mechanism in CSS is unclear. Cardiac hypertrophy in the current patient disappeared itself, but it could also be caused by premature closure of patent ductus arteriosus or patent foramen ovale.
      Our patient presented life-threatening cardiac hypertrophy after birth. The first rapid trio WES failed to identify the etiology because CSS was not in our cardiac or mitochondrial disease panels at that time. Additionally, autism, which is a more specific keyword, appeared only after 2 years of age. Sequencing data reanalysis yields as much as 10% because of the continuous improvement in knowledge.
      • Basel-Salmon L.
      • Orenstein N.
      • Markus-Bustani K.
      • et al.
      Improved diagnostics by exome sequencing following raw data reevaluation by clinical geneticists involved in the medical care of the individuals tested.
      Moreover, we recommend that CSS should be added to the cardiac panel of next-generation sequencing analysis.

      Declaration of competing interest

      The authors have no conflicts of interest relevant to this article.

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

      References

        • Nemani L.
        • Barik R.
        • Patnaik AN
        • Mishra RC
        • Rao AM
        • Kapur P.
        Coffin-Siris syndrome with the rarest constellation of congenital cardiac defects: a case report with review of literature.
        Ann Pediatr Cardiol. 2014; 7: 221-226
        • Alembik Y.
        • Roy E.
        • Hirsch E.
        • Tomb R.
        • Stoll C.
        Coffin-Siris syndrome with Lennox-Gastaut syndrome and hypertrophic cardiomyopathy. [Article in French].
        Ann Pediatr (Paris). 1988; 35: 491-494
        • Basel-Salmon L.
        • Orenstein N.
        • Markus-Bustani K.
        • et al.
        Improved diagnostics by exome sequencing following raw data reevaluation by clinical geneticists involved in the medical care of the individuals tested.
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