A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures (NEDMHS) is caused by homozygous mutation in the CPSF3 gene (606029) on chromosome 2p25.

Neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures (NEDMHS) is an autosomal recessive disorder characterized by global developmental delay and impaired intellectual development apparent from infancy. Affected individuals have hypotonia with poor or absent motor skills, feeding difficulties with poor overall growth, microcephaly, mild dysmorphic features, and early-onset seizures. Additional variable features, such as nystagmus, cortical blindness, and spasticity, may also occur. Patients with this disorder tend to have recurrent respiratory infections, likely due to aspiration, that may lead to death in childhood (Arnadottir et al., 2022).

Arnadottir et al. (2022) reported 6 patients from 3 unrelated families with a severe neurodevelopmental disorder apparent from early infancy. Patients A-D were of Icelandic descent (patients C and D were sibs and part of the extended family of patient A), and patients G and H were from a large family of Mexican descent. Two additional unrelated Icelandic patients (patients E and F) with a similar disorder were also identified, but they died early and genetic material was only available from the parents. Of the 8 patients reported, 5 died of pneumonia or respiratory failure between 1 and 7 years of age. The 3 living patients (patients B, G, and H) were 12 to 13 years of age. All patients had global developmental delay with severely impaired intellectual development, hypotonia, muscle atrophy, and feeding difficulties, often with failure to thrive and poor overall growth. All but 1 (patient F) had early-onset seizures, but patient F died at 1 year of age. A few patients had peripheral spasticity or 'cerebral palsy.' Additional variable features included nystagmus, strabismus, esotropia, gastroesophageal reflux, and constipation. Dysmorphic features included microcephaly, long face, high-arched palate, short upturned nose, and protruding teeth. Some patients were suspected to be blind. Brain imaging, when performed, showed nonspecific features, such as cerebral atrophy, thin corpus callosum, and cerebellar hypoplasia. Five patients had recurrent infections. Patients G and H, from the same Mexican family, developed seizures at 7 and 4 months of age. They had severe developmental delay with hypotonia, no head control, inability to sit, absent language, and minimal interaction with surroundings at 12 and 13 years of age. Other features included swallowing difficulties requiring tube feeding, peripheral neuropathy, spasticity, optic nerve atrophy, cortical blindness, nystagmus, osteopenia, and progressive hip contractures. Brain imaging in these patients showed progressive white matter loss, thin or atrophic corpus callosum, and T2-weighted hyperintensities.

The transmission pattern of NEDMHS in the families reported by Arnadottir et al. (2022) was consistent with autosomal recessive inheritance.

In 4 patients (patients A-D) from 2 Icelandic families with NEDMHS, Arnadottir et al. (2022) identified a homozygous missense mutation in the CPSF3 gene (G468E; 606029.0001). The mutation was initially found by analyzing whole-genome data from a large cohort of over 153,054 adult Icelandic individuals for a deficit of carriers of homozygous missense variants in different genes. The affected individuals with NEDMHS were then identified from a clinical cohort of Icelandic patients with various disorders who had undergone whole-genome sequencing. Samples from 2 additional deceased affected children of Icelandic descent (patients E and F) were not available, but the phenotype was similar to the other patients and the unaffected parents were heterozygous carriers. Western blot analysis of cells derived from patient B confirmed that the mutant protein was produced at normal levels, suggesting that the mutation causes a functional defect. The variant had a frequency of 0.41% in Iceland. Two further patients (G and H) from a large Mexican family with a homozygous missense variant in the CPSF3 gene (I354T; 606029.0002) were identified through the GeneMatcher program. Functional studies of the variants were not performed, but they were both predicted to disrupt the pre-mRNA cleavage mechanism, resulting in the accumulation of unprocessed pre-mRNA in cells, which would in turn activate a cellular stress response.