Adnp-Related Intellectual Disability And Autism Spectrum Disorder
Summary
Clinical characteristics.
ADNP-related intellectual disability and autism spectrum disorders (ADNP-related ID/ASD) are characterized by mild to severe intellectual disability and autism spectrum disorder (ASD). Of the 24 individuals reported to date, 23 were ascertained in cohorts with autism spectrum disorder (ASD) / intellectual disability (ID); one was identified in a clinical setting. The clinical information available on 12 of the 24 revealed: delayed developmental milestones (walking independently between 19 months and 4.5 years) and speech ranging from no words to sentences. ASD was characterized by stereotypic behavior and impaired social interaction. Other common findings include behavioral problems, sleep disturbance, hypotonia, seizures, feeding difficulties, visual problems (hypermetropia, strabismus, cortical visual impairment), and cardiac defects.
Diagnosis/testing.
The diagnosis of ADNP-related ID/ASD is established by identification of a heterozygous ADNP pathogenic variant on molecular genetic testing.
Management.
Treatment of manifestations: Treatment is symptomatic and can include: speech, occupational, and physical therapy; specialized learning programs depending on individual needs; treatment of neuropsychiatric features (e.g., sleep disorders, behavioral problems, and/or seizures); nutritional support as needed; routine treatment of ophthalmologic and cardiac findings.
Genetic counseling.
ADNP-related ID/ASD is expressed in an autosomal dominant manner. Given that all affected individuals with ADNP-related syndromic autism reported to date have the disorder as a result of a de novo ADNP pathogenic variant, the risk to other family members is presumed to be low. Prenatal testing and preimplantation genetic diagnosis are possible options.
Diagnosis
Formal diagnostic criteria have not been established.
Suggestive Findings
ADNP-related intellectual disability and autism spectrum disorders (ADNP-related ID/ASD) should be considered in individuals with the following clinical and MRI findings.
Clinical findings
- Mild-to-severe intellectual disability, including global developmental delay (motor – speech)
- Autism spectrum disorder (which can include behavioral problems and sleep disturbance)
- Characteristic facial appearance including prominent forehead, high anterior hairline, ptosis, up- or downslanted palpebral fissures, wide nasal bridge, and a thin vermilion of the upper lip. Many affected individuals have ear abnormalities, including small low-set ears, and protruding cup-shaped ears. See Figure 1.
Figure 1.
Photographs of affected males (ages: A. 9 yrs 7 mos; B. 5 yrs; C. 9 yrs 1 mo; D. 8 yrs 5 mos; E. 10 yrs 8 mos) showing the characteristic facial profile comprising a prominent forehead, high anterior hairline, ptosis, abnormal slant of palpebral fissures, (more...)
MRI findings. Atypical white matter lesions, wide ventricles, and choroid cysts. Note that these findings are not sufficiently distinct to specifically suggest the diagnosis of ADNP-related ID/ASD.
Note: Most individuals with ADNP-related ID/ASD are identified by use of a multigene panel or more comprehensive genomic testing in the context of evaluation of developmental delay, intellectual disability, and/ or autism spectrum disorder.
Establishing the Diagnosis
The diagnosis of ADNP-related ID/ASD is established in a proband with a heterozygous pathogenic variant in ADNP on molecular genetic testing (see Table 1).
Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:
- Single-gene testing. Sequence analysis of ADNP is performed first. To date, no partial or whole deletion of ADNP has been reported (see Molecular Genetics, Pathogenic variants); therefore, there is no evidence for performing gene-targeted deletion/duplication analysis if no pathogenic variant is found by sequence analysis.
- A multigene panel that includes ADNP and other genes of interest (see Differential Diagnosis) may also be considered. 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; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (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.
- More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes ADNP) fails to confirm a diagnosis in an individual with features of an ADNP-related ID/ASD. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in ADNP-Related Intellectual Disability and Autism Spectrum Disorder
| Gene 1 | Test Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by This Method |
|---|---|---|
| ADNP | Sequence analysis 3 | 24 / 24 4 |
| Gene-targeted deletion/duplication analysis 5 | None reported |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Coe et al [2014], De Rubeis et al [2014], Helsmoortel et al [2014], Pescosolido et al [2014], Vandeweyer et al [2014], Deciphering Developmental Disorders Study Group [2015]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Clinical Characteristics
Clinical Description
To date, a total of 23 individuals have been identified with a pathogenic variant in ADNP in several cohorts of patients with autism spectrum disorder/intellectual disability [Coe et al 2014, De Rubeis et al 2014, Helsmoortel et al 2014, Pescosolido et al 2014, Deciphering Developmental Disorders Study Group 2015]. One additional individual was identified in a diagnostic setting [Vandeweyer et al 2014].
In 12 of these 24 individuals, the clinical information available was sufficient to make the following preliminary generalizations about the phenotype. Of note, the oldest individual known to the authors to date is age 40 years [Author, personal observation].
Patients show a characteristic facial profile comprising a prominent forehead, high anterior hairline, ptosis, up- or downslanted palpebral fissures, wide nasal bridge, thin vermilion of the upper lip, and ear abnormalities including small low-set ears and protruding cup-shaped ears. Hand abnormalities are present, including clinodactyly, polydactyly, small fifth fingers, fetal finger pads, and prominent interphalangeal joints and distal phalanges. Several have truncal obesity (seen in 4 of 7 individuals assessed for this feature) and joint laxity (6/9).
Birth weight, length, and occipitofrontal circumference are all within the normal range. Infants often have hypotonia (9/12). Some children have seizures (2/12). Feeding difficulties and gastrointestinal problems are common (8/12), including decreased sucking or chewing, gastroesophageal reflux disease, and frequent vomiting and constipation.
All have mild to severe intellectual disability and autism spectrum disorder, characterized by stereotypic behavior and impaired social interaction.
Developmental milestones are delayed: sitting occurs between ages 7.5 and 12 months, and walking independently between 19 months and 4.5 years. Speech impairment is prominent (10/12), with expressive language ranging from no words to sentences. Bladder training is delayed in half of affected individuals.
Behavior problems may include anxiety, obsessive compulsive disorder, aggressive behavior, temper tantrums, attention deficient hyperactivity disorder (ADHD), and sleep problems.
More than half have visual problems, most commonly hypermetropia or strabismus. Two of 12 have cortical visual impairment.
Three of 12 have cardiac defects (atrial septal defect and mitral valve prolapse).
Most children have recurrent infections, including upper respiratory and urinary tract infections (7/11).
Genotype-Phenotype Correlations
With the limited number of affected individuals reported to date, no genotype-phenotype correlations can be made.
Penetrance
There is no evidence of reduced penetrance; all described pathogenic variants are de novo. The extent and severity of clinical findings vary among individuals.
Prevalence
The prevalence of pathogenic variants in ADNP is estimated at 0.17% of individuals with autism spectrum disorder (ASD) (95% binomial confidence interval: 0.083%-0.32%). It is one of the most common known single-gene causes of ASD [Helsmoortel et al 2014].
Differential Diagnosis
ADNP-related intellectual disability and autism spectrum disorders (ADNP-related ID/ASD) should be distinguished from other syndromes that include developmental delay, autism spectrum disorder, and distinctive facies; these include other chromatin remodeling disorders such as Kleefstra syndrome and Smith-Magenis syndrome, which share some findings with ADNP-related ID/ASD including autistic-like behavior with stereotypies, intellectual disability, and sleep disturbances. In both syndromes dysmorphic features differ slightly from those seen in ADNP-related ID/ASD.
- Kleefstra syndrome is characterized by intellectual disability, childhood hypotonia, and distinctive facial features. The majority of individuals function in the moderate to severe spectrum of intellectual disability, although a few individuals have mild delay and total IQ around 70. Although most have severe expressive speech delay with little speech development, general language development is usually at a higher level, making nonverbal communication possible. A complex pattern of other findings can also be observed including heart defects, renal/urologic defects, genital defects in males, severe respiratory infections, epilepsy/febrile seizures, autistic-like features in childhood, and extreme apathy or catatonic-like features after puberty.
- Smith-Magenis syndrome is characterized by distinctive physical features, developmental delay, cognitive impairment, and behavioral abnormalities. Infants have feeding difficulties, failure to thrive, hypotonia, hyporeflexia, prolonged napping or need to be awakened for feeds, and generalized lethargy. The majority of individuals function in the mild-to-moderate range of intellectual disability. The behavioral phenotype, including significant sleep disturbance, stereotypies, and maladaptive and self-injurious behaviors, is generally not recognized until age 18 months or older and continues to change until adulthood.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with ADNP-related intellectual disability and autism spectrum disorders (ADNP-related ID/ASD), the following evaluations are recommended:
- Physical examination to assess hypotonia, joint laxity, and obesity
- Anamnestic interview focusing on sleep problems and feeding difficulties
- Neurologic evaluation, including EEG if seizures are suspected, and brain MRI to detect brain abnormalities (if not performed as part of the diagnostic evaluation)
- In infants and children, comprehensive developmental assessment including gross and fine motor skills and speech and language; evaluation for autism spectrum disorder and intellectual disability
- Psychiatric evaluation if behavioral problems are present
- Ophthalmologic examination and vision assessment, including electrophysiologic and visual perception examination to detect cortical visual impairment
- Ultrasound of the heart to evaluate for cardiac anomalies
- Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations
Treatment is symptomatic; no specific therapy is available. Routine medical care by a pediatrician or primary care physician is recommended:
- Speech, occupational, and physical therapy
- Specialized learning programs depending on individual needs
- Treatment of any neuropsychiatric features including sleep disorders, behavioral problems, and/or seizures
- Nutritional support if necessary
- Routine treatment of cardiac and ophthalmologic findings
Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Administration of NAP, a neuroprotective octapeptide (NAPVSPIQ), has been reported to ameliorate some of the cognitive abnormalities observed in a knockout mouse model [Bassan et al 1999, Vulih-Shultzman et al 2007]. It restores learning and memory and reduces neurodegeneration in Adnp+/− mice. The drug name for NAP is davunetide, a candidate for treatment of multiple selected neurologic disorders. Intranasal and intravenous formulations of the drug have been shown to cross the blood-brain barrier. Phase II and Phase III clinical trials showed good tolerance without significant side effects. Although it is not known whether the disease is the result of a loss of function of ADNP and although the mouse model has not been evaluated for autistic traits, the observations raise hope for treatment in patients with an ADNP-related ID/ASD [Vandeweyer et al 2014].
Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions.