Clinical description.

Bryant-Li-Bhoj neurodevelopmental syndrome (BRYLIB) is characterized by developmental delay / intellectual disability (typically in the severe range) and nonspecific craniofacial abnormalities. Many affected individuals do not achieve independent sitting, walking, or speaking, although there is a range of developmental outcomes. The presentation is highly variable and can include hypotonia, epilepsy, other neurologic findings (spasticity, loss of developmental milestones, worsening gait, and/or camptocormia – forward flexion of the spine when standing that resolves when lying down), growth abnormalities (most commonly poor growth), craniosynostosis (of any suture), and ocular involvement. Congenital anomalies are rare but can include congenital heart defects, brain malformations, and genitourinary abnormalities in males.

Diagnosis/testing.

The diagnosis of BRYLIB is established in a proband with suggestive findings and a heterozygous pathogenic variant in either H3-3A (H3F3A) or H3-3B (H3F3B) identified by molecular genetic testing.

Management.

Treatment of manifestations: Feeding issues and poor weight gain may benefit from feeding therapy; in individuals with persistent feeding issues, gastrostomy tube may be considered. Standard treatment for developmental delay / intellectual disability, attention-deficit/hyperactivity disorder, autism spectrum disorder, anxiety, epilepsy, spasticity, constipation, craniosynostosis, vision issues, hearing loss, congenital heart defects, undescended testes, and hypothyroidism.

Surveillance: At each visit: measure growth parameters; assess nutrition safety and oral intake; monitor for constipation; assess for new manifestations, such as seizures and changes in tone and/or gait; monitor developmental progress and educational needs; and assess for behavioral issues, such as mobility and self-help skills. Annually or as clinically indicated: ophthalmology evaluation, audiology evaluation, and thyroid function tests.

Genetics counseling.

BRYLIB is expressed in an autosomal dominant manner and typically caused by a de novo H3-3A (H3F3A) or H3-3B (H3F3B) pathogenic variant. Therefore, the risk to other family members is presumed to be low. Once an H3-3A (H3F3A) or H3-3B (H3F3B) pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

Bryant-Li-Bhoj neurodevelopmental syndrome (BRYLIB) should be considered in individuals with the following clinical and brain MRI findings and family history.

Clinical findings

• Mild-to-profound developmental delay (DD) or intellectual disability (ID), most commonly in the severe range

AND

• Any of the following features:
  • Hypotonia
  • Microcephaly or macrocephaly
  • Craniosynostosis (of any suture) or abnormal head shape, excluding positional plagiocephaly
  • Poor growth with short stature
  • Epilepsy, including generalized myoclonic and tonic seizures, complex partial seizures, and tonic-clonic seizures
  • Spasticity
  • Progressive neurologic features, particularly loss of developmental milestones, worsening seizures, or worsening gait in adulthood
  • Camptocormia (forward flexion of the spine when standing that resolves when lying down; "bent spine") developing in adulthood
  • Ophthalmologic involvement, particularly strabismus or nystagmus
  • Nonspecific dysmorphic features (See Clinical Description.)
  • Minor congenital heart defects, most commonly atrial septal defect
  • Genitourinary anomalies in males, particularly cryptorchidism or retractile testes

Brain MRI findings

• Cortical atrophy
• Small posterior fossa

Family history. Because BRYLIB is typically caused by a de novo pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family).

Establishing the Diagnosis

The diagnosis of BRYLIB is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in H3-3A (H3F3A) or H3-3B (H3F3B), both of which encode histone H3.3, identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include likely pathogenic variants. (2) Identification of a heterozygous H3-3A or H3-3B variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing in a child with developmental delay or an older individual with intellectual disability may begin with chromosomal microarray analysis (CMA). Other options include use of a multigene panel or exome sequencing. Note: Single-gene testing (sequence analysis of H3-3A or H3-3B, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• An intellectual disability multigene panel that includes H3-3A or H3-3B and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition in a person with a nondiagnostic CMA while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the relative recent description (2020) and rarity of BRYLIB, some panels for intellectual disability may not include these genes. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used and yields results similar to an intellectual disability multigene panel, with the additional advantage that exome sequencing includes genes recently identified as causing intellectual disability, whereas some multigene panels may not.
  Genome sequencing is also possible.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

Bryant-Li-Bhoj neurodevelopmental syndrome (BRYLIB) is characterized by developmental delay / intellectual disability and nonspecific craniofacial abnormalities. The presentation is highly variable and can include hypotonia, epilepsy, other neurologic findings (spasticity, loss of developmental milestones, worsening gait, and/or camptocormia), poor growth, and ocular involvement. Congenital anomalies are rare but can include congenital heart defects and genitourinary abnormalities in males.

To date, 57 unrelated individuals have been identified with a pathogenic variant in H3-3A (H3F3A) or H3-3B (H3F3B) [Maver et al 2019, Bryant et al 2020, Okur et al 2021]. The following description of the phenotypic features associated with this condition is based on these reports.

Developmental delay (DD) and intellectual disability (ID). All individuals with BRYLIB have some degree of developmental delay or intellectual disability, typically in the severe range. Affected individuals usually experience delays in both gross motor skills and speech development, but some only experience one or the other. However, there is a wide range of developmental outcomes.

• About 78% of affected individuals have delayed independent sitting (achieved after age 8 months) or have not achieved independent sitting (older than age 8 months and still unable to sit independently). The delay can be profound. The oldest affected individual to achieve independent sitting began sitting independently at age seven years.
• About 93% of affected individuals were either delayed in achieving independent walking (achieved after age 16 months) or have not achieved that milestone (older than age 16 months and not walking independently). This milestone can be achieved very late. One affected individual began independently walking at age eight years.
• About 52% of affected individuals are nonverbal, with an additional 40% experiencing speech delay.

Developmental regression can occur in a minority of affected individuals. Regression is not continuous and is not always associated with seizures. Although developmental regression is typically mild, it can be severe, such that children who were previously able to walk and talk can lose those abilities.

Other neurodevelopmental features

• Hypotonia is common but may resolve in some individuals as they age. Occasionally hypotonia can evolve into hypertonia.
• Infant feeding difficulties have been described in about 25% of affected individuals. Most are treated with a nasogastric tube or gastrostomy tube.
• Spasticity typically involves the legs. Spasticity typically develops in childhood and is associated with either hypotonia or hypertonia. Hypertonia tends to be limited to limbs, while hypotonia can be seen in other parts of the body.
• Camptocormia. All reported adults have had a new subacute onset of motor issues in the third decade of life that generally remains stable after onset. This affects their ability to walk independently and has significant impact on their gait.

Epilepsy. About half of individuals with a heterozygous pathogenic variant in HD-3A or H3-3B have epilepsy.

• Onset is generally in infancy or childhood.
• The type of seizure disorder is variable and includes myoclonic and tonic epilepsy, partial or complex partial seizures, and tonic-clonic seizures.
• Seizure frequency is highly variable, with some individuals having relatively few seizures and others experiencing progressively more frequent seizures or status epilepticus.
• Some individuals with seizures are well controlled on medication while others are refractory to treatment (see Management).

Behavioral issues. Behavioral issues can include autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). Happy demeanor and stereotypic flapping of hands has also been noted in some affected individuals.

Growth is impacted in about half of all affected individuals.

• Weight
  • Poor weight gain was reported in eight infants.
  • Weight is typically less affected than length/height, with only four individuals being more than two standard deviations below the mean for their age and sex in terms of weight.
  • However, six individuals were at least two standard deviations above the mean for their age and sex.
• Length/height
  • Short stature was observed in 22 individuals.
  • Tall stature was seen in three individuals.
• Head circumference
  • Congenital microcephaly was seen in 19 individuals.
  • Four individuals had congenital macrocephaly and two had relative macrocephaly.

Craniosynostosis / abnormal head shape (excluding positional plagiocephaly) has been described in about one third of affected individuals. The presentation is variable, and no specific sutures have been identified as being more likely to be involved. Brachycephaly, dolichocephaly, and sagittal craniosynostosis have all been observed.

Ophthalmologic involvement. Strabismus is present in slightly more than one third of affected individuals, and nystagmus is present in a small minority of affected individuals (7%). Difficulty or inability to fixate and/or track was seen in about 9% of affected individuals. Interestingly, 5% have cortical visual impairment.

Neuroimaging. The most common finding on brain MRI is small posterior fossa (72%) [Alves et al 2022], with the next most common finding being cortical malformations (44%), which can include diffuse dysgyria, anterior pachygyria, and/or simplified cortical appearance. Brain malformations do not appear to correlate with any other clinical features, including seizures or craniosynostosis.

• Malformation of the corpus callosum, including hypoplasia and agenesis, can also be seen (28%).
• About 25% of affected individuals show evidence of hypomyelination or delayed myelination.
• Chiari I malformations were seen in 4/18 (22%) of individuals imaged.

Genitourinary abnormalities in males. About 35% of affected males have cryptorchidism. Retractile testes have also been observed.

Other associated features

• Cardiovascular abnormalities. Atrial septal defect was seen in about 16% of individuals with BRYLIB.
• Gastrointestinal issues. Chronic constipation was reported in 26% of affected individuals.
• Hearing loss. A subset of affected individuals have been reported with mild-to-moderate congenital hearing loss. This is thought to be static.
• Endocrinology. Hypothyroidism has been reported in a subset of affected individuals.
• Facial features. No specific dysmorphic features have been observed. If present, dysmorphic features are nonspecific.

Prognosis. It is unknown whether life span in BRYLIB is abnormal. Based on current data, life span is not limited by this condition, as several adults have been reported. Data on possible progression of behavior abnormalities or neurologic findings are still limited.

Phenotype Correlations by Gene

There is no difference in the phenotype regardless of whether the pathogenic variant is in H3-3A or H3-3B.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified for either H3-3A or H3-3B.

Prevalence

Germline pathogenic variants in H3-3A and H3-3B are rare and have been reported in 57 individuals to date. There are no specific populations with increased risk for these pathogenic variants.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with BRYLIB, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

There is no cure for BRYLIB.

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Bryant-Li-Bhoj neurodevelopmental syndrome (BRYLIB) is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• All probands reported to date with BRYLIB whose parents have undergone molecular genetic testing have the disorder as the result of a de novo H3-3A (H3F3A) or H3-3B (H3F3B) pathogenic variant.
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is known to have the H3-3A or H3-3B pathogenic variant identified in the proband, the risk to the sibs of inheriting the variant is 50%. However, to date all known cases have been de novo.
• If the H3-3A or H3-3B pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].

Offspring of a proband.

• Individuals with BRYLIB are not known to reproduce; however, many are not yet of reproductive age.

Other family members. Given that all probands with BRYLIB reported to date have the disorder as a result of a de novo H3-3A or H3-3B pathogenic variant, the risk to other family members is presumed to be low.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Risk to future pregnancies is presumed to be low as the proband most likely has a de novo H3-3A or H3-3B pathogenic variant. There is, however, a recurrence risk (~1%) to sibs based on the theoretic possibility of parental germline mosaicism [Rahbari et al 2016]. Given this risk, prenatal and preimplantation genetic testing may be considered.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Histone H3.3 plays an important role in both development (stem cells) and in postmitotic cells, such as neurons [Cox et al 2012, Funk et al 2022]. H3.3 is the only replication-independent form of H3 and therefore is the main form of H3 in postmitotic cells. Histone H3.3 is incorporated into the nucleosome, where it helps provide structure to chromatin and regulate gene expression [Jang et al 2015, Shi et al 2017]. While all reported pathogenic variants in H3-3A and H3-3B result in the same phenotype, the specific way in which individual pathogenic variants alter H3.3 function varies [Bryant et al 2020, Okur et al 2021]. Pathogenic missense variants can completely abolish binding to chaperone proteins or alter post-translational modifications [Elsässer et al 2012, Trovato et al 2020].

Mechanism of disease causation. The mechanism of disease causation is currently unknown.

H3-3A (H3F3A)- or H3-3B (H3F3B)-specific laboratory technical considerations. Most literature describing variants in H3-3A and H3-3B or orthologous genes in other organisms do not include the initiating methionine when indicating amino acid changes. This includes Bryant et al [2020]. Care should be taken when using primary literature to determine which numbering nomenclature is being used.

Author Notes

Dr Bryant's work focuses on studying the pathogenic mechanism of missense variants in H3-3A (H3F3A) and H3-3B (H3F3B). Dr Bhoj's research is focused on discovering new human disease genes, their pathogenic mechanism, and potential treatments.

Revision History

• 28 September 2023 (ma) Review posted live
• 17 January 2023 (lb) Original submission

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