A number sign (#) is used with this entry because of evidence that Bryant-Li-Bhoj neurodevelopmental syndrome-1 (BRYLIB1) is caused by heterozygous mutation in the H3F3A gene (601128) on chromosome 1q42.

Bryant-Li-Bhoj neurodevelopmental syndrome-1 (BRYLIB1) 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 abnormal head shape, 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).

Genetic Heterogeneity of Bryant-Li-Bhoj Neurodevelopmental Syndrome

See also BRYLIB2 (619721), caused by heterozygous mutation in the H3F3B gene (601058).

Bryant et al. (2020) reported 33 unrelated patients with a similar neurodevelopmental disorder who were ascertained through exome or genome sequencing from several clinical and research centers. Most of the patients were children, although there were a few teenagers and 1 patient was 32 years of age. All had moderate to severe global developmental delay and impaired intellectual development, usually with hypotonia, delayed walking or inability to walk, and poor or absent speech. Rare patients showed developmental regression. Three patients died in the first years of life. About of a third of patients had poor overall growth and short stature. Feeding problems, such as gastroesophageal reflux, were sometimes observed, and 10 patients required a feeding tube. Laryngomalacia was observed in 4 patients. Some patients had hypertonia or peripheral spasticity; the oldest patient had spastic paraplegia. Ten patients had unilateral or bilateral hearing loss. Seventeen patients had various types of seizures, including generalized, myoclonic, tonic, complex partial, and focal. The severity was variable: some had only a single seizure or febrile seizures that were well-controlled, whereas a few had refractory seizures. Most (22) patients had nonspecific abnormalities on brain imaging, including enlarged ventricles, hypoplastic or thin corpus callosum, and hypomyelination. About half of patients had an abnormal head shape with craniosynostosis, microcephaly or macrocephaly, brachycephaly, plagiocephaly, and dolichocephaly. Dysmorphic facial features were common, although there was not a distinct gestalt. Notable findings included prominent forehead, sloped forehead, bitemporal narrowing, flat midface, hypertelorism, deep-set eyes, epicanthal folds, low-set or posteriorly rotated ears, arched or thick eyebrows, flat or depressed nasal bridge, small or large nose, abnormal philtrum, slanted palpebral fissures, micrognathia, retrognathia, open mouth, and thin or tented upper lip. More than half of patients had oculomotor abnormalities, mainly strabismus, exotropia, and nystagmus; a few had tracking problems. Some patients had skeletal anomalies, including distal defects of the hands and feet, scoliosis, kyphosis, joint contractures, and bell-shaped thorax. Less common features included atrial septal defects, cryptorchidism, and chronic constipation. None of the patients developed cancer.

Okur et al. (2021) reported the clinical details of 4 unrelated patients (patients 1-4), ranging from 4.5 to 28 years of age, with global developmental delay, abnormal ataxic or wide-based gait, speech delay, and hypotonia. Three patients showed failure to thrive in infancy. All had short stature, 3 had microcephaly, and 1 had macrocephaly. Two patients had spasticity of the lower limbs and 2 had seizures. Three were reported to have a happy demeanor. Brain imaging, performed in 2 patients, showed abnormalities in 1: decreased white matter, hypomyelination, and enlarged ventricles. Three patients had variable dysmorphic facial features, including facial asymmetry, upslanting palpebral fissures, esotropia, strabismus, midface hypoplasia, synophrys, hypotelorism, open mouth with full lips, low-set ears, pointed chin, and prognathia. Skeletal anomalies included camptodactyly, small hands and feet, joint hypermobility, pes planus, and scoliosis. Two had chronic constipation. The patients were described retrospectively after exome sequencing identified mutations in the H3F3A gene.

The heterozygous mutations in the H3F3A gene that were identified in patients with BRYLIB1 by Bryant et al. (2020) occurred de novo.

In 33 unrelated patients with BRYLIB1, Bryant et al. (2020) identified de novo heterozygous missense mutations in the H3F3A gene (see, e.g., 601128.0001-601128.0005). The mutations, which were found by whole-exome or genome sequencing, occurred throughout the gene. All but 1 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 that in 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.

In 6 unrelated patients with BRYLIB1, Okur et al. (2021) identified 6 different de novo heterozygous missense mutations at highly conserved residues in the H3F3A gene (see, e.g., 601128.0003; 601128.0004; 601128.0006-601128.0007). 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, whereas 1 (R41C; 601128.0006) increased protein levels compared to controls. Additional functional studies of some of the variants showed that 1 (R129H; 601128.0007) had a significantly stronger interaction with DAXX (603186) compared to controls, which might lead to aberrant transcription. 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.

Bryant et al. (2020) noted that zebrafish with a dominant D123N mutation in the h3f3a gene developed craniofacial abnormalities. Homozygous knockdown of the h3f3a gene resulted in a loss of neural crest-derived jaw cartilages. There was also a partial reduction in Foxd3 (611539)-derived cranial glia, melanocytes, and xanthophores; those injected with dominant-negative h3f3a showed a further reduction in these cell types.