Clinical characteristics.

Most individuals with HNRNPH2-related neurodevelopmental disorder (HNRNPH2-NDD) have symptoms early in life, before age 12 months. The major features of HNRNPH2-NDD are developmental delay / intellectual disability, motor and language delays, behavioral and psychiatric disorders, and growth and musculoskeletal abnormalities. Minor features include dysmorphic facies, gastrointestinal disturbances, epilepsy, and visual defects. Although HNRNPH2-NDD is an X-linked condition, there is not enough information on affected females versus affected males to make any generalizations about phenotypic differences between the two sexes.

Diagnosis/testing.

The diagnosis of HNRNPH2-NDD is established in a proband with suggestive clinical findings and a heterozygous or hemizygous pathogenic (or likely pathogenic) variant in HNRNPH2 identified by molecular genetic testing.

Management.

Treatment of manifestations: Feeding therapy or gastrostomy tube placement for those with poor weight gain; standard treatment for developmental delay / intellectual disability, behavioral problems, epilepsy, movement disorders, abnormal tone, constipation, sleep apnea, cortical visual impairment, hearing loss, musculoskeletal anomalies, cardiac defects, and pubertal anomalies.

Surveillance: At each visit: measurement of growth parameters; evaluation of nutritional status, feeding issues, and safety of oral intake; assessment of developmental progress and educational needs; behavioral assessment; assessment for new manifestations (seizures, change in tone, movement disorders, developmental regression); monitoring for evidence of sleep disturbance and signs/symptoms of sleep apnea; orthopedic assessment, including for scoliosis (until skeletal maturity or in older individuals who are nonambulatory). Assess for hip dysplasia in infancy or at each visit in individuals who are nonambulatory. At each visit in childhood and adolescence: assessment for signs/symptoms of puberty. At least annually or as clinically indicated: hearing evaluation (in childhood); ophthalmologic evaluation.

Genetic counseling.

HNRNPH2-NDD is inherited in an X-linked manner. Most affected individuals have the condition as the result of a de novo pathogenic variant. If the mother of the proband has an HNRNPH2 pathogenic variant, the chance of the mother transmitting it in each pregnancy is 50%. Females who inherit the pathogenic variant are at high risk of being affected. Males who inherit the pathogenic variant have a variable phenotype ranging from severe manifestations to mild developmental delay with autistic features and psychiatric diagnoses. A male with a mosaic HNRNPH2 pathogenic variant that includes the germline may transmit the HNRNPH2 pathogenic variant to daughters but not to sons. Prenatal and preimplantation genetic testing are possible if the familial pathogenic variant has been identified.

Suggestive Findings

HNRNPH2-NDD should be considered in both females and (less commonly) males with the following clinical features.

Clinical findings

• Developmental delay / intellectual disability, most often characterized by significant motor abnormalities with severe expressive and receptive language impairment
  AND
• Any of the following features in infancy or childhood:
  • Developmental regression
  • Generalized hypotonia of infancy
  • Infant feeding difficulties
  • Acquired microcephaly
  • Poor growth
  • Movement disorders, such as hand stereotypies
  • Epilepsy, of variable semiology
  • Behavioral problems and psychiatric issues including anxiety, attention-deficit/hyperactivity disorder, sensory issues, social communication disorder, or autism spectrum disorder
  • Nonspecific dysmorphic features (See Clinical Description.)
  • Ophthalmologic involvement including strabismus and cortical visual impairment

Family history. Because HNRNPH2-NDD is typically caused by a de novo pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family). Rarely, the family history may be consistent with X-linked inheritance (e.g., no male-to-male transmission).

Establishing the Diagnosis

The diagnosis of HNRNPH2-NDD is established in a proband with suggestive clinical findings and a heterozygous or hemizygous pathogenic (or likely pathogenic) variant in HNRNPH2 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 HNRNPH2 variant of uncertain significance does not establish or rule out the diagnosis of this disorder.

Because the phenotype of HNRNPH2-NDD is indistinguishable from many other inherited disorders with developmental delay / intellectual disability, recommended molecular genetic testing approaches include use of a multigene panel or comprehensive genomic testing.

Note: Single-gene testing (sequence analysis of HNRNPH2, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• An intellectual disability / autism multigene panel that includes HNRNPH2 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition 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. (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 is likely involved. Exome sequencing is most commonly used; 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

Most individuals with HNRNPH2-related neurodevelopmental disorder (HNRNPH2-NDD) have symptoms early in life, before age 12 months. The major features of HNRNPH2-NDD are developmental delay / intellectual disability, motor and language delays, behavioral and psychiatric disorders, and growth and musculoskeletal abnormalities. Minor features include dysmorphic facies, gastrointestinal disturbances, epilepsy, and visual defects.

To date, 49 individuals from 45 families with pathogenic variants in HNRNPH2 have been identified [Harmsen et al 2019, Jepsen et al 2019, Somashekar et al 2020, Bain et al 2021, Gillentine et al 2021, White-Brown et al 2022]. Initially, because the only affected individuals were phenotypic females presumed to be 46,XX, it was hypothesized that affected 46,XY individuals were embryonic lethal. However, at least 16 affected 46,XY individuals have now been reported [Harmsen et al 2019, Jepsen et al 2019, Gillentine et al 2021, Somashekar et al 2020, Bain et al 2021, Kreienkamp et al 2022].

At least one unaffected mother of an affected female was found to have the same HNRNPH2 pathogenic variant as her daughter. This unaffected mother had significantly skewed X-chromosome inactivation [White-Brown et al 2022]. There is not enough information on affected females versus affected males to make any generalizations about phenotypic differences between the two sexes.

Developmental delay (DD) and intellectual disability (ID) has been reported in all affected individuals and is one of the major phenotypic features of HNRNPH2-NDD. The degree of disability is most commonly in the moderate-to-severe range.

• Speech and language is severely affected, with the majority of affected individuals being nonverbal or minimally verbal and others with speech apraxia or difficulties with articulation. In those who acquired speech, most did so between ages one and five years.
• Most affected individuals have delays in the acquisition of both gross and fine motor skills in infancy. Many affected individuals are nonambulatory. All affected individuals significantly benefit from intensive therapy services, and many also use orthoses in addition to other devices. Referral to a rehabilitation specialist / physiatrist and orthopedist is recommended for appropriate supports. Most individuals require significant support in daily activities.
• Many affected individuals have low cognitive skills and low adaptive skill sets using the Vineland Adaptive Behavior Scales. Most cognitive scales show floor effects below the first centile for many testing domains of standardized cognitive assessment. Most individuals require special education and support in daily activities into adulthood.

Behavioral and psychiatric problems have been validated with formal testing in almost half (47%) of affected individuals.

• The most common diagnoses include anxiety (68%), self-injurious behaviors (38%), and autism spectrum disorder (34%).
• Attention-deficit/hyperactivity disorder was diagnosed in about 15% of affected individuals, but a higher number of caregivers reported concerns regarding attention, hyperactivity, and distractibility.
• Some affected individuals demonstrated stereotypies and intermittent developmental regression that can be suggestive of Rett syndrome (see MECP2 Disorders).

Other neurodevelopmental features

• Abnormal muscle tone. Most affected individuals have abnormalities of tone (most commonly hypotonia but also hypertonia), often first observed before age 12 months. Spasticity / muscle rigidity has been noted in about 33% of affected individuals. Some affected individuals have been given a clinical diagnosis of cerebral palsy based on their tone and muscle issues.
• Weakness. Most affected individuals have generalized muscle weakness and decreased muscle bulk.
  • Electromyography done on one affected individual showed selective lower extremity denervation.
  • Of three affected individuals who underwent muscle biopsy, two were found to have abnormalities and the third was normal. One affected individual was found to have mild type II fiber atrophy; the other affected individual had reduced activity in the respiratory chain enzymes in complexes II and III.
• Movement disorders. Reported abnormal movements have included the following:
  • Motor planning problems
  • Ataxia
  • Stereotypies
  • Clumsiness
  • Abnormal gait
• Intermittent developmental regression. Caregivers have reported regression during episodes of illness or after a clinical seizure, followed by recovery of the lost skill once the episode resolves.

Seizures have been reported in about 39% of affected individuals, and another 10% have abnormal EEG findings without any known clinical correlation. One affected individual had refractory seizures. In general, affected individuals have responded well to levetiracetam and valproic acid (see Management).

• The average age of presentation of first seizure is 8.7 years (range: age 3-34 years).
• The semiology of clinical seizures is variable.
  • Staring episodes (69%) are the most common seizure type.
  • Febrile seizures are present in 23% of affected individuals.
  • Other seizure semiologies include tonic-clonic (43%), tonic (38%), spasms (23%), clonic (15%), and myoclonic (15%).
• Abnormal EEG findings include diffuse slowing of the background, left-sided posterior and midline epileptic discharges, and paroxysmal activity in the right temporal lobe.

Neuroimaging. Brain MRI is normal in most affected individuals who have undergone imaging; however, some individuals have nonspecific findings, including delayed myelination, decreased cerebellar volume (cerebellar hypoplasia), and abnormal corpus callosum (thinning, dysgenesis, and vertical configuration). Two affected individuals underwent MR spectroscopy, with one showing a lactate peak in the basal ganglia region; the other MR spectroscopy was interpreted as normal.

Respiratory. Three affected individuals have been noted to have breath-holding spells, but in general HNRNPH2-NDD has not been associated with significant respiratory issues.

Sleep disturbances have been observed and are associated with problems falling and staying asleep. Melatonin has been effective in treating these concerns in many affected individuals (see Management) [Author, personal observation]. The sleep disturbances seen in individuals with HNRNPH2-NDD are more likely to be related to issues with sleep onset and maintenance as opposed to sleep apnea.

Growth. Four affected individuals were noted to have intrauterine growth restriction on prenatal ultrasound, but most have anthropometric measurements within the normal range for sex at birth. It should be noted that occipital frontal circumference (OFC) was not available for all affected individuals.

• Weight. About half of reported affected individuals (55%) had difficulty gaining weight, which in most cases was attributed to feeding difficulties during infancy (see Gastrointestinal issues in the text following).
• Length/height. Six out of 33 affected individuals were reported to be short for their age and sex, with the shortest individual being 5.5 SD below the mean.
• Head circumference. About 30% of affected individuals have acquired microcephaly (defined as OFC ≥2 SD below the mean for age and sex). The most severely affected individual had an OFC 4.08 SD below the mean.

Gastrointestinal issues are present in most affected individuals. Feeding problems and chronic constipation are the two most common problems.

• Feeding difficulties have been observed in more than two thirds of affected individuals.
  • Most affected individuals have reported feeding issues before age 12 months, with some having concerns immediately after birth.
  • About 34% of affected individuals have dysphagia accompanied by aspiration.
  • Many affected individuals have persistent feeding issues, along with poor growth, throughout life. Several have required placement of feeding tubes.
• Other gastrointestinal issues
  • Poor appetite
  • Gastroesophageal reflux disease
  • Swallowing difficulty (dysphagia)
  • Pica
  • Diarrhea
  • Overeating, which can lead to weight gain in rare affected individuals
  • Abdominal pain
  • Bloating

Vision involvement. A considerable proportion (67%) of affected individuals have visual defects, with strabismus being the most common finding in about 54%. Other findings include cortical visual impairment (33%), myopia (17%), and decreased visual acuity (13%). One individual was reported to have congenital ptosis.

Hearing deficits have been reported by parents in one quarter of affected individuals, but the type of hearing loss (sensorineural, conductive, or mixed) is not known for many of these reported individuals. Recurrent ear infections and tinnitus have also been reported.

Other associated features

• Orthopedic abnormalities have been reported in individuals of all ages and most commonly include:
  • Pes planus
  • Arachnodactyly
  • Scoliosis, including kyphosis and lordosis, which is most frequently neuromuscular in origin
  • Hip dysplasia
  Rarer findings include:
  • Navicular bone drop with calcaneal adduction
  • Bone, muscle, and joint pain
  • Arthritis and stiffness of joints
• Cardiovascular abnormalities. Nonspecific cardiac abnormalities have been observed in four affected individuals, including two with mitral valve prolapse, one with congenital aortic dilatation, and one with an atrial septal defect.
• Endocrine. One affected individual had precocious puberty and three had delayed puberty.
• Facial features. No recognizable dysmorphic features have been observed. If present, dysmorphic features are nonspecific. Such features may include:
  • Almond-shaped eyes
  • Short palpebral fissures
  • Short philtrum
  • Long columella
  • Hypoplastic alae nasi
  • Full lower lip
  • Micrognathia
• Stroke. One affected individual had a stroke after a first-time seizure at age 34 years. It is unclear if early stroke is a rare finding in affected individuals or if this was a rare co-occurrence of two unrelated findings.

Prognosis. It is unknown whether the life span in HNRNPH2-NDD is abnormal. One reported individual was alive at age 38 years [Bain et al 2021], demonstrating that survival into adulthood is possible. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported. Based on the available data, the clinical course does not appear to be progressive or degenerative into early adulthood.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Prevalence

The overall prevalence remains unknown; to date, 49 individuals from 45 families have been reported with this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with HNRNPH2-NDD, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Evaluation of Relatives at Risk

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

Therapies Under Investigation

No targeted therapies are approved or under investigation for use in HNRNPH2-NDD at this time. A natural history study of individuals with hnRNP-related disorders is currently under way (NCT03492060).

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

HNRNPH2-related neurodevelopmental disorder (HNRNPH2-NDD) is an X-linked disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a female proband

• Almost all females reported to date with HNRNPH2-NDD represent simplex cases (i.e., a single occurrence in the family).
• Rarely, a female diagnosed with HNRNPH2-NDD has the disorder as the result of a pathogenic variant inherited from a mother (vertical transmission from a hemizygous father to a female proband has not been reported to date).
  • Vertical transmission of an HNRNPH2 pathogenic variant from a heterozygous unaffected mother (with skewed X-chromosome inactivation) to her affected daughter has been reported [White-Brown et al 2022].
  • Affected male and female sibs born to consanguineous parents are presumed to have HNRNPH2-NDD as the result of a pathogenic variant inherited from a mother with germline mosaicism [Somashekar et al 2020].
• Molecular genetic testing of the parents is recommended to confirm parental genetic status and to allow reliable recurrence risk assessment.
• The mother of a proband who is found to be heterozygous for an HNRNPH2 pathogenic variant may have favorably skewed X-chromosome inactivation that results in her being unaffected or mildly affected [White-Brown et al 2022].
• 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 [Somashekar et al 2020].

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

• If the mother of the proband has an HNRNPH2 pathogenic variant, the chance of the mother transmitting it in each pregnancy is 50%.
  • Females who inherit the pathogenic variant are at high risk of being affected; however, a female with favorably skewed X-chromosome inactivation may be unaffected or have a mild phenotype [White-Brown et al 2022]. (See Clinical Description.)
  • Males who inherit the pathogenic variant will be affected. Hemizygous males have variable phenotypes ranging from severe manifestations (described in 11 of the 16 affected males reported to date) to only mild developmental delay with autism spectrum disorder and psychiatric diagnoses (described in five males) [Kreienkamp et al 2022].
• If the father of the proband has a mosaic HNRNPH2 pathogenic variant, all his daughters are at risk of inheriting the pathogenic variant; his sons are not at risk of inheriting the pathogenic variant.
• If a female proband represents a simplex case and if the HNRNPH2 pathogenic variant cannot be detected in the leukocyte DNA of either parent, the risk to sibs is approximately 1% because of the possibility of parental mosaicism [Somashekar et al 2020, Kreienkamp et al 2022].

Parents of a male proband

• The father of an affected male will not have the disorder, nor will he be hemizygous for the HNRNPH2 pathogenic variant; therefore, he does not require further evaluation/testing.
• If a male is the only affected family member, the mother may be a heterozygote, the affected male may have a de novo HNRNPH2 pathogenic variant (in which case the mother is not a heterozygote), or the mother may have somatic/germline mosaicism. Fourteen * of the 16 males with HNRNPH2-NDD reported to date have the disorder as the result of a de novo pathogenic variant.
   * Including monozygotic twin males [Kreienkamp et al 2022]
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.

Sibs of a male proband. The risk to sibs depends on the genetic status of the mother:

• If the proband represents a simplex case and the HNRNPH2 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal germline mosaicism [Somashekar et al 2020, Kreienkamp et al 2022].
• If the mother of the proband has an HNRNPH2 pathogenic variant, the chance of transmitting it in each pregnancy is 50%.
  • Females who inherit the pathogenic variant are at high risk of being affected; however, a female with favorably skewed X-chromosome inactivation may be unaffected or have a mild phenotype [White-Brown et al 2022]. (See Clinical Description.)
  • Males who inherit the pathogenic variant will be affected. Hemizygous males have variable phenotypes ranging from severe manifestations (described in 11 of the 16 males reported to date) to only mild developmental delay with autism spectrum disorder and psychiatric diagnoses (described in 5 males) [Kreienkamp et al 2022].

Offspring of a proband

• Females with an HNRNPH2 pathogenic variant have a 50% chance of transmitting the pathogenic variant to each child. Affected females are not known to reproduce.
• Affected males are not known to reproduce.

Other family members. The risk to other family members depends on the genetic status of the proband's mother: if the mother has a pathogenic HNRNPH2 pathogenic variant, her family members may be at risk.

Note: Molecular genetic testing may be able to identify the family member in whom a de novo pathogenic variant arose, information that could help determine genetic risk status of the extended family.

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 young adults who are heterozygotes or who are at increased risk of being heterozygotes.

Prenatal Testing and Preimplantation Genetic Testing

Once the HNRNPH2 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

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

Heterogeneous nuclear ribonucleoproteins (HNRNPs) are a group of proteins that bind to RNA and have multiple roles in RNA metabolism, including transcription, splicing, translation, transfer to the cytoplasm, and mRNA stability and decay. There are more than 20 HNRNPs, designated HNRNP A-U. Pathogenic variants affecting the genes that encode the HNRNPs result in various neurodevelopmental and neurodegenerative disorders [Bain et al 2016, Geuens et al 2016, Bain et al 2021, Gillentine et al 2021, Kreienkamp et al 2022].

HNRNPH2 is located on the X chromosome at Xq22.1. The 449-amino-acid protein product has five domains including three quasi-RNA-recognition motifs (RRMs) and two glycine-rich domains (GRD). The GRDs are essential for the nuclear localization of the protein. A highly conserved nuclear localization sequence (NLS) between amino acids 194 and 220 has been recognized to interact with transportin 1 (Trn1), a nuclear transport receptor.

HNRNPH2 is expressed ubiquitously and its protein product is largely found in the cytoplasm. HNRNPH2 is predominantly involved in alternative splicing of the pre-mRNA and acting as a shuttle between the nucleus and the cytoplasm. Most pathogenic variants are located within or near the NLS.

Mechanism of disease causation. The specific mechanism leading to disease is unknown; a toxic gain-of-function mechanism has been proposed (see bioRxiv).

Consistent with this, more than 90% of individuals with HNRNPH2-related neurodevelopmental disorder have the condition as a result of a pathogenic missense variant located either adjacent to or within the NLS. The two most common pathogenic variants are c.616C>T (p.Arg206Trp) and c.617G>A (p.Arg206Gln) (NM_019597.5 / NP_062543.1) [Bain et al 2016, Geuens et al 2016, Bain et al 2021, Kreienkamp et al 2022].

Author Notes

See HNRNPH2-Related Disorders.

Acknowledgments

We would like to thank the families who are affected by HNRNPH2-related neurodevelopmental disorder for sharing their personal stories. We appreciate their participation in the ongoing natural history study (NCT03492060) to better understand the disorder. We are appreciative of the support of the two patient advocacy groups Yellow Brick Road Project and To Cure a Rose Foundation.

Dr Bain would like to personally thank the first research assistant to work on this project, Ms Olivia Thornburg. The natural history study would not be as successful without her dedication and hard work.

Revision History

• 15 September 2022 (ma) Review posted live
• 1 June 2022 (sm) Original submission

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