The proband (3 years 7 months old; Figure 1A and B) is the firstborn male child of healthy non-consanguineous parents. Family history was unremarkable, with no undue exposure to teratogens reported. The pregnancy was complicated by imminent preterm labour at 32 weeks of gestation. The patient was born at 34 weeks of gestation with the umbilical cord wrapped around his neck and green amniotic fluid. The propositus head circumference, weight, and length at birth were 34 cm (90th centile), 2275 g (50th centile), and 49 cm (90th centile), respectively. On delivery, his Apgar scores at 1 minute and 5 minutes were 8 and 8, respectively. He was apneic at birth and was intubated for several days. He also received nasogastric tube feeding to circumvent swallowing issues. A brain magnetic resonance imaging (MRI) examination performed at 1.5 months of age showed mildly hypoplastic inferior vermis, slight dilatation of the lateral ventricles, and dilated fourth ventricle (Figure 1C and D). Brain MRI examination has not revealed anomalies of olfactory bulb, optic nerves, or pituitary gland. At 4 months of age, a gastrostomy tube was placed. Multiple congenital birth defects were observed soon after birth. An echocardiogram identified a small atrial septal defect, while a brain ultrasonographic assessment revealed inferior vermian hypoplasia. Bilateral choroid coloboma involving the optic nerves was diagnosed by an ophthalmologist at 13 months. Surgical correction was performed for a congenital umbilical hernia and a congenital hernia at the linea alba. Bilateral sensorineural hearing loss was managed with hearing aids. Hypoglycemic episodes started to manifest at approximately 9 months of age, and therapy with slow release cornstarch was initiated. Notably, there has also been clear psychomotor delay as the proband could sit without support by 15 months of age and walk independently at 37 months of age. His first teeth erupted at 14 months of age. The boy has no expressive language. At 2 years 8 months old, his psychomotor development was evaluated to be in the range of 3 (self-help) to 10 (fine motor) months according the Diagnostic Inventory for Screening Children (DISC) scale. In addition, he was diagnosed with autism spectrum disorder at 2 years 9 months of age. During his last examination, at the age of 3 years 7 months, his weight was 11.5 kg (<3rd centile) and his height was 88 cm (<3rd centile). He had a prominent metopic ridge, smaller and wide right ear, sacral dimple, clinodactyly of the 5th fingers, micropenis, and cryptorchidism. He was still suffering from laryngomalacia and severe feeding problems necessitating gastrostomy tube feeding. Frequent feeds and uncooked cornstarch every 6 hours was used to prevent hypoglycemic episodes. In summary, the proband presents with 3 major and 5 minor features of CHARGE syndrome (Table 1) combined with additional features.
As no cytogenetic alterations were identified, we assessed the genome of the proband and his parents by WES. We identified a de novo 18 nucleotides duplication in exon 31 of the CHD7 gene (c.6341_6358dup, p.Asp2119_Pro2120ins6); NM_017780; NP_060250; MIM 214800) confirmed by Sanger sequencing (Figure 1E), which affects an evolutionary constrained region (Figure 1F). Modelization of the putatively encoded mutated protein suggests that the insertion of this chain of 6 amino acid residues potentially substitutes a linear chain into a short alpha helix (Figure 1G). The other deleterious de novo variants, which contribute to the current patient phenotype, were not identified. All unique de novo variants identified for this proband are listed in Table 2.