A number sign (#) is used with this entry because of evidence that Brunet-Wagner neurodevelopmental syndrome (BRUWAG) is caused by homozygous or compound heterozygous mutation in the RBL2 gene (180203) on chromosome 16q12.

Brunet-Wagner neurodevelopmental syndrome (BRUWAG) is an autosomal recessive disorder characterized by infantile hypotonia and severely impaired development affecting both motor and cognitive skills. Affected individuals either do not achieve independent ambulation or walk with an unsteady gait; those who walk may lose the ability due to spasticity of the lower limbs. They have absent language, poor or absent social skills, and behavioral abnormalities. Most have variable ocular findings, including nystagmus, strabismus, optic atrophy, myopia, or hypermetropia (summary by Brunet et al., 2020 and Samra et al., 2021).

Brunet et al. (2020) reported 2 sibs, born of unrelated parents, with a severe neurodevelopmental disorder apparent from early childhood. The patients, who were 17 and 15 years of age, had hypotonia in early infancy and began crawling around 2 years of age, but never achieved independent ambulation. They had severe developmental delay with impaired intellectual development, no social interaction, absent speech, and stereotypic and autoaggressive behavior. Both had nystagmus; additionally, the older sister had strabismus and the younger brother had optic atrophy. The younger brother had a more severe clinical course, showing developmental regression associated with the onset of refractory myoclonic seizures at age 10 years. Minor dysmorphic features, including hypertelorism, thin eyebrows, and full lips, were observed. Brain imaging showed supra- and infratentorial atrophy and hyperostosis of the skull; the brother had a thin corpus callosum. They did not have microcephaly.

Samra et al. (2021) reported 3 patients from 2 unrelated consanguineous families of Druze and Kurdish descent, respectively, with a severe neurodevelopmental disorder. The patients presented in infancy with hypotonia and global developmental delay. They achieved walking with an unsteady, but not ataxic, gait between 2 and 9 years of age. Two patients from family 1 developed lower limb spasticity and became wheelchair-bound at 6 and 30 years, respectively. The patients had profound intellectual disability with only a few words or absent speech. Two patients had onset of well-controlled seizures at 4 and 20 years. There were variable ocular abnormalities, including strabismus, hypermetropia, corneal clouding, myopia, anisometropia, and astigmatism. Hearing was normal. Two unrelated patients had progressive microcephaly (down to -4.7 SD). Other features included sleep disturbances and irritability.

The transmission pattern of BRUWAG syndrome in the family reported by Brunet et al. (2020) was consistent with autosomal recessive inheritance.

In 2 sibs, born of unrelated parents, with BRUWAG syndrome, Brunet et al. (2020) identified compound heterozygous putative loss-of-function mutations in the RBL2 gene (180203.0001 and 180203.0002). The mutations, which were found by exome sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed.

In 3 patients from 2 unrelated consanguineous families with BRUWAG syndrome, Samra et al. (2021) identified homozygous loss-of-function mutations in the RBL2 gene (180203.0003 and 180203.0004) that segregated with the disorder in both families. The mutations were found by exome sequencing and confirmed by Sanger sequencing. Detailed studies of fibroblasts derived from patients in family 1 did not reveal abnormal expression of DNA methyltransferases, did not show DNA methylation abnormalities compared to controls, and did not indicate changes in telomere length or growth characteristics, suggesting that the pathogenesis of the disorder is likely due to another specific function of the RBL2 gene.