Clinical characteristics.

HNRNPU-related neurodevelopmental disorder (HNRNPU-NDD) is characterized by developmental delay and intellectual disability – typically moderate to severe – with speech and language delay and/or absent speech. Affected individuals may also display autistic features. There may be feeding difficulties during the neonatal period as well as hypotonia, which often remains lifelong. Dysmorphic features have been described but they are nonspecific. Affected individuals are likely to experience seizures (most commonly tonic-clonic or absence) that may be refractory to treatment. Nonspecific brain MRI findings include ventriculomegaly and thinning of the corpus callosum. Less common findings include cardiac abnormalities, strabismus, undescended testes in males, renal anomalies, and skeletal features, including joint laxity, polydactyly, and scoliosis. Rarely, abnormal breathing patterns, including hyperventilation and apnea, may be present and can lead to sleep disturbance.

Diagnosis/testing.

The diagnosis of HNRNPU-NDD is established in a proband with suggestive findings and a heterozygous pathogenic variant in HNRNPU identified by molecular genetic testing.

Management.

Treatment of manifestations: Standard treatment of seizures with anti-seizure medications (sodium valproate is often used and is frequently effective); consider instituting the ketogenic diet and/or newer generation anti-seizure medications in those with refractory seizures. Feeding therapy; consider a temporary or permanent feeding tube for those with persistent feeding issues. Consider supplemental oxygen, CPAP, or BiPAP in those with sleep apnea. Standard treatment for tone abnormalities, intellectual disability, behavioral problems, hyperventilation / abnormal breathing patterns, congenital heart defects, strabismus, hearing loss, renal anomalies, undescended testes, and limb defects.

Surveillance: At each visit: measurement of growth parameters; evaluation of nutritional status and safety of oral intake; monitor for evidence of constipation, new seizures, hyperventilation, apnea, and changes in tone; assessment of developmental progress and behavior. Annually or as clinically indicated: ophthalmologic and audiologic evaluations.

Agents/circumstances to avoid: Activities and agents that may induce seizures.

Genetic counseling.

HNRNPU-NDD is expressed in an autosomal dominant manner and typically caused by a de novo HNRNPU pathogenic variant. The risk to other family members is hypothesized to be low. Presumed parental germline mosaicism has been reported in one family with two affected sibs. Once the HNRNPU pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic testing are possible.

Suggestive Findings

HNRNPU-NDD should be considered in individuals with the following clinical and brain MRI findings.

Clinical findings (presenting in infancy or childhood). Moderate-to-severe developmental delay (DD) or intellectual disability (ID) AND any of the following:

• Generalized hypotonia of infancy
• Infant feeding difficulties
• Speech and language delay and/ or absent speech
• Autism spectrum disorder or autistic traits
• Nonspecific dysmorphic facial features (See Clinical Description.)
• Epilepsy, including generalized tonic-clonic seizures and absence seizures
• Short stature
• Strabismus

Brain MRI findings. The most common brain MRI findings are nonspecific but include:

• Ventriculomegaly
• Thinning of the corpus callosum

Family history. Because HNRNPU-NDD is typically caused by a de novo pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family). However, a report of two affected sibs suggests the possibility of germline mosaicism in a parent [Durkin et al 2020] (see Genetic Counseling).

Establishing the Diagnosis

The diagnosis of HNRNPU-related neurodevelopmental disorder is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in HNRNPU identified by molecular genetic testing (see Table 1).

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

Molecular genetic testing in a child with developmental delay or an older individual with intellectual disability often begins with chromosomal microarray analysis (CMA). If CMA is not diagnostic, the next step is typically either a multigene panel or exome sequencing. Note: Single-gene testing (sequence analysis of HNRNPU, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including HNRNPU) that cannot be detected by sequence analysis.
• An intellectual disability or epileptic encephalopathy multigene panel that includes HNRNPU 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 rarity of HNRNPU, some panels for intellectual disability may not include this gene. (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 ID multigene panel with the additional advantage that exome sequencing includes genes recently identified as causing ID and/or epileptic encephalopathy 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

To date, 83 individuals have been identified with a pathogenic variant in HNRNPU [Caliebe et al 2010, Need et al 2012, Thierry et al 2012, Allen et al 2013, de Kovel et al 2016, Bramswig et al 2017, Depienne et al 2017, Leduc et al 2017, Yates et al 2017, Durkin et al 2020, Song et al 2021, Taylor et al 2022]. The following description of the phenotypic features associated with this condition is based on these reports.

Developmental delay (DD) and intellectual disability (ID), typically affecting all developmental domains and falling into the moderate-to-severe range, have been found in all reported individuals to date.

• Speech delay is common and most reported individuals are nonverbal, although ascertainment bias against more mildly affected individuals may have skewed this finding to the more severe end of the HNRNPU-related neurodevelopmental disorder (HNRNPU-NDD) spectrum.
• Limited speech and ability to speak in short sentences has been described in some individuals.
• To date, most individuals have required special educational provisions, although children with HNRNPU-NDD may be able to attend a mainstream school with dedicated support.
• The vast majority of reported adults have required assisted living, which has allowed them some degree of independence.

Other neurodevelopmental features

• Hypotonia is a common feature seen in about 80% of individuals with HNRNPU-NDD, especially during the neonatal period and in early infancy, and may persist into later childhood and adulthood. With time, some individuals may develop hypertonia leading to spasticity.
• Infant feeding difficulties are observed in about 58% of affected individuals. The severity of feeding difficulties varies considerably and could be attributed to a combination of gastroesophageal reflux, hypotonia, and oromotor dysfunction, with some children requiring long-term gastrostomy tube insertion, while in others feeding may be improved with the use of temporary nasogastric tube feeding.
• Seizures are seen in around 95% of reported individuals, with more than 90% presenting with their first seizure before age 24 months.
  • About 60% of individuals have generalized tonic-clonic seizures; 44% have absence seizures.
  • Rarer types of seizures have included the following: two individuals with West syndrome [Bramswig et al 2017, Leduc et al 2017]; one individual with Lennox-Gastaut syndrome [Leduc et al 2017]; and one individual with Doose syndrome [Hinokuma et al 2020].
  • Most affected individuals have seizures as a presenting feature along with developmental delay.
  • Seizures often respond to standard anti-seizure medication, although some may require more than one anti-seizure medication or a trial of such medications to attain reasonable seizure control.
  • Ketogenic diet and newer medications to control seizures have been trialed (see Management).
• Sleep disturbance is a common finding, with some affected individuals reported to have sleep apnea, warranting a sleep study and further evaluation to establish a cause.

Respiratory abnormalities. Some affected individuals have abnormal breathing patterns. At least two have been reported with hyperventilation and apnea [Shimada et al 2018, Spagnoli et al 2021]. Other findings have included breath-holding episodes and irregular breathing patterns (particularly at night) that coincide with sleep disturbances.

Behavioral issues. More than half of affected individuals have significant behavioral, social, and communication difficulties with substantial impact on the individuals and their families.

• About one third meet the formal clinical diagnostic criteria of an autism spectrum disorder, whereas others have autistic-like features.
• In contrast, some are described as having a very friendly, placid personality.
• Less common behavioral phenotypes included obsessive-compulsive disorder and self-stimulatory behaviors.
• Other associated behaviors (more rarely seen):
  • Aggressive or destructive behavior
  • Hand flapping
  • Agitation
  • Hyperventilation episodes (See also Respiratory abnormalities.)
  • Attention-deficit disorder

Dysmorphic features. No dysmorphic features that are specific to HNRNPU-NDD have been observed. If present, dysmorphic features are nonspecific. Features described in the literature include the following:

• Abnormal head shape (frontal bossing, microcephaly, dolichocephaly)
• Prominent forehead
• Highly arched, thin eyebrows
• Palpebral fissure abnormalities (both upslanted and downslanted)
• Epicanthus
• Thin vermilion of the upper lip
• Low-hanging columella
• Widely spaced teeth

Growth. Proportionate short stature has been observed in about 50% of individuals for whom data have been reported; further studies are required to determine the cause. One individual had microcephaly.

Cardiac issues. Nineteen individuals with cardiac abnormalities have been described. The following have been reported, in order from most to least frequent:

• Atrial septal defect
• Ventricular septal defect
• Patent ductus arteriosus
• Tricuspid atresia, tetralogy of Fallot, aortic dilatation, and transposition of the great arteries together in one affected individual

Eyes. About 30% of affected individuals have strabismus. Hypermetropia has been described in at least two individuals.

Abnormalities of genitalia. Undescended testis is reported in approximately 20% of affected males.

Neuroimaging. There do not appear to be uniform findings on brain imaging in affected individuals that would specifically suggest this diagnosis; similarly, a normal brain MRI would not preclude this as a diagnosis.

• Of 62 individuals reported in the literature who had a brain MRI imaging, 38 (61%) had abnormalities noted.
• The most common abnormality was ventriculomegaly, followed by thinning of the corpus callosum.

Other associated features, seen in fewer than 10% of individuals:

• Hearing loss. Two individuals with HNRNPU-NDD and sensorineural hearing impairment have been reported.
• Renal abnormalities. Anatomic renal abnormalities are more likely to be seen in individuals with 1q44 deletion (see Genetically Related Disorders). About 8% of individuals with HNRNPU-NDD have renal issues including agenesis of the kidney, unilateral multicystic kidney, and renal pelvic ectasia.
• Musculoskeletal features are rare [Thierry et al 2012, Depienne et al 2017, Leduc et al 2017, Durkin et al 2020]:
  • Joint hyperlaxity (in 8 individuals)
  • Butterfly vertebrae (1 individual) and scoliosis (3 individuals)
  • Polydactyly, including bilateral postaxial polydactyly of the hand (1 individual) and preaxial polydactyly of the right foot (3 individuals)
  • Cutaneous syndactyly of fingers 2 and 3
  • Fifth digit clinodactyly
  • Hallux valgus

Prognosis. It is unknown whether life span in HNRNPU-NDD is abnormal. Based on current data, life span is not significantly limited by this condition, as several adults have been reported. Data on possible progression of behavior abnormalities or neurologic findings are still emerging. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Prevalence

The prevalence of this condition is unknown. To date, approximately 83 individuals with HNRNPU-NDD have been reported.

Evaluations Following Initial Diagnosis

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

Treatment of Manifestations

Surveillance

Agents/Circumstances to Avoid

Avoid activities and agents that may induce seizures, as the majority of affected individuals have a seizure disorder.

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Sustained single-dose gene therapy treatments for genetic forms of epilepsy, including HNRNPU-NDD, are currently being explored. This approach will be based on developing mRNA therapies and/or using a viral vector, such as AAV-9 (adeno-associated vector serotype 9), to deliver therapeutic protein to treat those forms of epilepsy caused by haploinsufficiency of proteins such as HNRNPU.

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.

Mode of Inheritance

HNRNPU-related neurodevelopmental disorder (HNRNPU-NDD) is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• Most probands reported to date with HNRNPU-NDD whose parents have undergone molecular genetic testing have the disorder as the result of a de novo HNRNPU pathogenic variant.
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• 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. Presumed parental mosaicism has been reported in one family with two affected sibs [Durkin et al 2020].
    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 the HNRNPU pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [Durkin et al 2020].

Offspring of a proband

• Each child of an individual with HNRNPU-NDD has a 50% chance of inheriting the HNRNPU pathogenic variant.
• Individuals with HNRNPU-NDD are not known to have reproduced; however, many are not yet of reproductive age.

Other family members. Given that most probands with HNRNPU-NDD have the disorder as the result of a de novo HNRNPU 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 HNRNPU pathogenic variant. There is, however, a recurrence risk to sibs based on the possibility of parental germline mosaicism [Durkin et al 2020]. 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

HNRNPU, located on 1q44, encodes for HNRNPU, which is a DNA- and RNA-binding protein. It is involved in nuclear chromatin organization, telomere-length regulation, mRNA alternative splicing and stability, Xist-mediated transcriptional silencing, and mitotic cell cycle regulation. Additionally, it negatively regulates glucocorticoid-mediated transcriptional activation and participates in circadian regulation [Hasegawa et al 2010, Bi et al 2013, Nozawa et al 2017, Havrilla et al 2019]. Thierry et al [2012] showed that HNRNPU is expressed in at least six different tissues: adult brain, heart, kidney, liver, cerebellum, and fetal brain, with the strongest expression in the cerebellum.

De novo loss-of-function variants in HNRNPU can lead to a disease phenotype characterized by a variable neurodevelopmental syndrome with moderate-to-severe intellectual disability, seizures, behavioral abnormalities, and agenesis of the corpus callosum. A study by Leduc et al [2017] in which whole-exome sequencing was used suggested that haploinsufficiency was the main mechanism of pathogenicity.

Mechanism of disease causation. Loss of function

Author Notes

In the area of pediatric dysmorphology / genomic medicine, Dr Balasubramanian has led several studies focused on genotype-phenotype correlation in newly identified genes from next-generation sequencing studies such as the Deciphering Developmental Disorders (DDD) study, and has several first/senior author articles published in this area on large cohorts of individuals with new syndromal diagnoses. Her research is now focused on exploring disease mechanisms and establishing international registries for these disorders to better understand the natural history of these conditions. Dr Balasubramanian has published the largest cohort of people so far with HNRNPU-related neurodevelopmental disorder and has gathered phenotypic data on more than 50 individuals with HNRNPU-related neurodevelopmental disorder. She has also written the Unique patient support group information leaflet on the condition along with Anna Pelling from Unique (rarechromo.org).

Dr Balasubramanian's web pages: www.sheffield.ac.uk and www.mellanbycentre.org

Acknowledgments

Dr Balasubramanian would like to thank all the families and their clinicians who have so far contributed to ongoing HNRNPU research, and the HNRNPU-related neurodevelopmental disorder patient support group for all their help and contribution in understanding more about the natural history of this condition. Dr Balasubramanian would also like to thank and acknowledge trainees in Dr Balasubramanian's group: Michael Yates, Anna Durkin, and James Taylor, who have contributed to the medical literature on HNRNPU.

Revision History

• 10 March 2022 (ma) Review posted live
• 22 September 2021 (mb) Original submission

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