Non-polyalanine repeat mutation in PHOX2B is detected in autopsy cases of sudden unexpected infant death

Abstract

Background Congenital central hypoventilation syndrome (CCHS), which is caused by PHOX2B with phenotypic variations, has a point of controversy: CCHS is putatively involved in autopsy cases of sudden unexpected infant death (SUID) including sudden infant death syndrome. Objective The relation of CCHS to SUID cases was investigated by extensive genotyping of PHOX2B. Methods We analyzed 93 DNA samples of less than one-year-old SUID cases that were autopsied in our department. Unrelated adult volunteers (n = 942) were used as the control. Results No polyalanine tract expansion was detected in the SUID cases. The allelic frequencies of repeat contractions and SNP (rs28647582) in intron 2 were not significantly different from that in those control group. Further extensive sequencing revealed a non-polyalanine repeat mutation (NPARM) of c.905A>C in a sudden death case of a one-month-old male infant. This missense mutation (p.Asn302Thr), registered as rs779068107, was annotated to ‘Affected status is unknown’, but it might be associated with the sudden death. Conclusion NPARM was more plausibly related to sudden unexpected death than expansions because of severe clinical complications. This finding indicates possible CCHS involvement in forensic autopsy cases without ante-mortem diagnosis.

Molecular autopsy for sudden death in Japan

“…As described above, variation in the serotonin transporter gene is famously considered a cause of sudden infant death 45,71,72 ; ACADM, PHOX2B, eNOS, SCN5A, NOS1AP, TNNI3, CPT2, and LQTSrelated gene variants have also been analyzed in this context 31,46,47,49,50,[73][74][75][76] . In the following section, representative cases that we experienced are described.…”