The proband was born in 2007, weighing 2,600 g with 49 cm in length after a gestation period of 39 weeks. The patient was weak and susceptible to illness as a child. A heart murmur was detected in the patient at a local hospital at the age of 1. For further treatment, his family requested hospitalization when he was 3 years old. After examination, he was diagnosed with HHS (patent ductus arteriosus, persistent left superior vena cava, and congenital absence of left arm radius) (Figures 1A, 2A). PDA ligation under general anesthesia was performed in the patient, and the procedure was successful (Figure 1B). After obtaining consent from the patient's parents, we recruited their blood and inquired about their family and previous medical history (Figure 3A). In addition, craniofacial dysmorphisms were observed in the patient. Ten years later, we visited the patient and inquired about his physical and study conditions in detail. At the time of the visit, the patient was 152 cm tall, weighed 42 kg, and was able to communicate normally. His grades were between 20 and 40 in all subjects (total score 100-120/subject), near the bottom of his class. According to the latest version of "the height and weight percentile table of Chinese people aged 0-18 years" released by the Capital Pediatric Research Institute, the height and weight of the proband were lower than 90 and 80% of the same age group (13.5 years old), respectively. Mild intellectual disability (IQ 59) was detected using the Wechsler Intelligence Scale. An imbalance of the dorsal muscles was observed (Figure 2B). Combined with sequencing results, we concluded that the proband had BAF-opathies.
Given that the patient's clinical diagnosis was heart-hand syndrome, we screened the TBX5, SALL4, and LMNA genes, but no deleterious variation was found. Subsequently, targeted sequencing, including a panel of genes associated with congenital heart disease, was performed on the patient.
Whole-exome sequencing was conducted to generate 12.4 GB data with 99% coverage and a depth of >100 x in this patient. After data filtration, a novel heterozygous variant of ACTL6A (NM_004301, c.478_478delT; p.F160Lfs*9) was identified. This variant led to frameshift sequences and a premature termination codon, potentially affecting the features of the resulting proteins. According to the nonsense-mediated mRNA decay theory, this variant may induce the decay of ACTL6A mRNA in patients. Bioinformatics analysis predicted that this variant was deleterious.
Sanger sequencing was performed to validate this variant (Figure 3B). Cosegregation analysis showed that this is a de novo variant and does not exist in the 1,000 Genome Browser, ExAC Browser, Exome Variant Server, gnomAD browser, or 200 unrelated ethnically matched healthy controls. The amino acid sequence was highly conserved (Figure 3C). There is a large distinction between the standard and mutant protein models constructed with SWISS-MODEL, which may affect the assembly of the BAF complex (Figure 3D).