A number sign (#) is used with this entry because of evidence that Bryant-Li-Bhoj neurodevelopmental syndrome-2 (BRYLIB2) is caused by heterozygous mutation in the H3F3B gene (601058) on chromosome 17q25.

Bryant-Li-Bhoj neurodevelopmental syndrome-2 (BRYLIB2) is a highly variable phenotype characterized predominantly by moderate to severe global developmental delay with impaired intellectual development, poor or absent speech, and delayed motor milestones. Most patients have hypotonia, although some have peripheral hypertonia. Common features include variable dysmorphic facial features, oculomotor abnormalities, feeding problems, and nonspecific brain imaging abnormalities. Additional features may include hearing loss, seizures, short stature, and mild skeletal defects (summary by Bryant et al., 2020).

For a discussion of genetic heterogeneity of Bryant-Li-Bhoj neurodevelopmental syndrome, see BRYLIB1 (619720).

Bryant et al. (2020) reported 13 patients (patients 34-46), ranging from 7 months to 18 years of age, with a similar neurodevelopmental disorder who were ascertained through exome or genome sequencing from several clinical and research centers. All had moderate to severe global developmental delay with delayed walking or inability to walk, impaired intellectual development, and poor or absent speech. Five patients had short stature or failure to thrive, whereas 2 had macrosomia. Most had hypotonia, and about half had peripheral hypertonia with spasticity. The severity was highly variable: patient 44 was nonverbal and unable to walk at age 18 years, whereas patient 46 had normal development and IQ, but demonstrated an expressive language disorder and had onset of seizures at age 10 years. Three patients had evidence of disease progression. In all, 7 patients had variable types of seizures, which were refractory and severe in a few patients. Brain imaging showed cortical atrophy, hypomyelination, and thin corpus callosum in some patients. Many patients had abnormal head shape, including microcephaly, macrocephaly, brachycephaly, plagiocephaly, and dolichocephaly. Most, but not all, had dysmorphic facial features, including midface hypoplasia, protruding chin, downslanting palpebral fissures, low-set, posteriorly rotated, or large ears, prominent forehead, open mouth expression, low or high nasal bridge, low columella, deep-set eyes, bushy eyebrows, and anteverted nostrils. Some had skeletal anomalies, including scoliosis, hemivertebrae, flat feet, and joint defects. A few patients had cryptorchidism; 2 had hypothyroidism.

Okur et al. (2021) reported 6 unrelated patients (patients 5-10), ranging from 5 to 33 years of age, with BRYLIB2. The patients had hypotonia, feeding difficulties, and global developmental delay. Most had short stature. Three had microcephaly, 2 had gait abnormalities, and 2 had seizures. Brain imaging was normal in 3, but patient 5 had leukoencephalopathy, and patient 8 had cortical dysplasia with hypoplasia of the corpus callosum and cerebellum. Dysmorphic features included plagiocephaly, dolichocephaly, prominent forehead, flat facial profile, midface hypoplasia, deep-set eyes, downslanting palpebral fissures, long eyelashes, thin upper lip, dental anomalies, depressed nasal bridge, micro- or prognathia, bitemporal narrowing, smooth philtrum, and large posteriorly rotated ears. Despite the facial findings, there was not a clear facial gestalt. Ocular anomalies included strabismus, nystagmus, esotropia, myopia, and retinal degeneration with dysplastic optic nerve. One patient had laryngomalacia and sensorineural hearing loss. Variable skeletal findings included foot deformities, high-arched palate, scoliosis, joint contractures, and joint hypermobility. Two patients had constipation. Two had hypothyroidism, 1 had type I diabetes mellitus, 1 had precocious puberty, and 2 had advanced bone age.

The heterozygous mutations in the H3F3B gene that were identified in patients with BRYLIB2 by Bryant et al. (2020) occurred de novo.

In 13 unrelated patients with BRYLIB2, Bryant et al. (2020) identified de novo heterozygous mutations in the H3F3B gene (see, e.g., 601058.0001-601058.0004). The mutations, which were found by whole-exome or genome sequencing, occurred throughout the gene. All but 1 were missense variants, and all were absent from the gnomAD database. In vitro studies of lymphoblasts or fibroblasts derived from a subset of patients showed that the distribution of posttranslational modification (PTM) histone abundances was similar to controls. The overall histone PTM variation was slightly increased in controls compared to patients. Nonetheless, some histone PTMs were altered in patients compared to controls. The findings suggested that mutant histones can be incorporated into the nucleosome and cause local deregulation of the chromatin state with modest alterations in the control of histone modification. This could affect multiple histone functions, including gene expression, chromatin stability, DNA damage repair, and differentiation. RNA sequencing of a subset of pooled patient cells showed upregulation of genes involved in mitosis, and in vitro studies of pooled patient fibroblast lines showed increased cellular proliferation compared to controls; viability of patient cells was similar to controls. In silico molecular modeling of the mutations suggested 3 broad scenarios for the variants' impact: disruption of H3.3 DNA binding; disrupted formation of the histone octamer or binding with other histones; and disruption of histone-protein binding to chaperones or other interacting proteins. There were no genotype/phenotype correlations. None of the patients developed cancer.

In 6 unrelated patients with BRYLIB2, Okur et al. (2021) identified 6 different de novo heterozygous mutations at highly conserved residues in the H3F3B gene (see, e.g., 601058.0001 and 601058.0005). The mutations, which were found by exome sequencing, were absent from the gnomAD database. Expression of a subset of variants in HEK293 cells showed that some resulted in decreased protein levels. The mutant proteins localized normally to the nucleus. Molecular modeling suggested that some, but not all, mutations might alter the PTMs of histone H3.3. The possible molecular pathomechanism of other mutations was unclear.