A number sign (#) is used with this entry because of evidence that congenital central hypoventilation syndrome-2 and autonomic dysfunction (CCHS2) is caused by homozygous mutation in the MYO1H gene (614636) on chromosome 12q24. One such family has been reported.

Congenital central hypoventilation syndrome-2 and autonomic dysfunction (CCHS2) is an autosomal recessive disorder characterized by shallow breathing and apneic spells apparent in the neonatal period. Affected infants require mechanical ventilation due to impaired ventilatory response to hypercapnia, as well as tube feeding due to poor swallowing, aspiration, and gastrointestinal dysmotility. Some patients have other features of autonomic dysfunction, including bladder dysfunction, sinus bradycardia, and temperature dysregulation. Although mild global developmental delay with learning difficulties and seizures were present in the single family reported, it was unclear if these features were related to the hypoventilation phenotype (Spielmann et al., 2017).

For a discussion of genetic heterogeneity of CCHS, see CCHS1 (209880).

Spielmann et al. (2017) reported 3 sibs, born of consanguineous parents with Native American background, with central hypoventilation apparent from early infancy. The patients presented in the neonatal period with alveolar hypoventilation, shallow breathing, and apnea, requiring mechanical ventilation initially during sleeping but later also while awake. They lacked a ventilatory response to high levels of CO2, necessitating tracheostomy. All 3 infants also had feeding difficulties with gastroesophageal reflux, aspiration, autonomic features of esophageal and intestinal dysmotility, and achalasia, requiring tube feeding. One infant died at 11 months of age, whereas the other 2 patients were alive at 8 and 15 years. The oldest patient had additional signs of autonomic dysfunction, including sinus bradycardia, temperature dysregulation, and bladder dysfunction requiring catheterization. She also had kyphoscoliosis with restrictive lung disease, a nonspecific myopathy, strabismus, myopia, and astigmatism. Both older patients had global developmental delay with hypotonia and poor walking, but were able to attend special education schools. These 2 older patients also developed well-controlled seizures at ages 4 and 15, respectively. Spielmann et al. (2017) noted that these additional findings, such as seizures and developmental delay, may be unrelated to the hypoventilation disorder. A fourth sib, who was heterozygous for the MYO1H mutation, had mild breathing and swallowing difficulties in infancy, but had no admissions to the ICU or evidence of oxygen desaturation; this individual was considered to be unaffected.

The transmission pattern of CCHS2 in the family reported by Spielmann et al. (2017) was consistent with autosomal recessive inheritance.

In 3 sibs, born of consanguineous parents of Native American descent, with CCHS2, Spielmann et al. (2017) identified a homozygous frameshift mutation in the MYO1H gene (614636.0001). The mutation, which was found by a combination of linkage analysis and whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the ExAC database. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in nonsense-mediated mRNA decay and a loss of function. PHOX2B (603851) mutations had been excluded in these patients. Mutations in the MYO1H gene were not identified in 23 additional individuals with symptoms of central hypoventilation who were negative for PHOX2B testing, suggesting that MYO1H mutations are not a common cause of the disorder.

Spielmann et al. (2017) found that homozygous loss of Myo1h in mice caused neonatal feeding problems, cyanosis, and poor respiration, resulting in death within the first 4 hours of birth. This was associated with marked deficits in ventilatory parameters and an attenuated response to hypercapnia compared to controls.