Clinical characteristics.

ADNP-related disorder is characterized by hypotonia, severe speech and motor delay, mild-to-severe intellectual disability, and characteristic facial features (prominent forehead, high anterior hairline, wide and depressed nasal bridge, and short nose with full, upturned nasal tip) based on a cohort of 78 individuals. Features of autism spectrum disorder are common (stereotypic behavior, impaired social interaction). Other common findings include additional behavioral problems, sleep disturbance, brain abnormalities, seizures, feeding issues, gastrointestinal problems, visual dysfunction (hypermetropia, strabismus, cortical visual impairment), musculoskeletal anomalies, endocrine issues including short stature and hormonal deficiencies, cardiac and urinary tract anomalies, and hearing loss.

Diagnosis/testing.

The diagnosis of ADNP-related disorder 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; nutritional support as needed; standard treatment of gastrointestinal, ophthalmologic, musculoskeletal, endocrine, and cardiac findings; standard treatments for hearing loss, seizures, urinary tract anomalies, and recurrent infections.

Surveillance: At each visit monitor growth and nutrition, occupational and physical therapy needs; assess for seizures, developmental progress, behavioral issues, gastrointestinal issues, and family needs; annual vision assessment.

Genetic counseling.

ADNP-related disorder is expressed in an autosomal dominant manner and typically caused by a de novo ADNP pathogenic variant, the risk to other family members is presumed to be low. Once an ADNP pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic testing are possible.

Suggestive Findings

ADNP-related disorder should be considered in individuals with the following clinical and MRI findings.

Clinical findings

• Severe speech and motor delay
• Mild-to-severe intellectual disability
• Autism spectrum disorder, additional behavioral problems, and sleep disturbance
• Characteristic facial appearance including prominent forehead, high anterior hairline, downslanted palpebral fissures, prominent eyelashes, ear malformations, wide and depressed nasal bridge, short nose with full, upturned nasal tip, long philtrum, thin vermilion of the upper lip, pointed chin, and widely spaced teeth. See Figure 1.
• Feeding difficulties and gastrointestinal problems (e.g., gastroesophageal reflux disease, lack of satiation, frequent vomiting, constipation)
• Vison issues (e.g., strabismus, cortical visual impairment, hypermetropia) and various ophthalmologic defects
• Musculoskeletal anomalies (e.g., joint laxity, hand and foot anomalies, pectus deformities, plagiocephaly)
• Other features: endocrine manifestations, cardiac and renal anomalies, hearing loss, seizures, recurrent infections

Figure 1.

Facial features of individuals with ADNP pathogenic variants. Frontal and lateral views. Note the prominent forehead with high anterior hairline, the wide and depressed nasal bridge, and short nose with full, upturned nasal tip [Van Dijck et al 2019]. (more...)

MRI findings include atypical white matter lesions, wide ventricles, corpus callosum underdevelopment, cerebral atrophy, cortical dysplasia, and choroid cysts. Note that these findings are not sufficiently distinct to specifically suggest the diagnosis of ADNP-related disorder.

Establishing the Diagnosis

The diagnosis of ADNP-related disorder is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in ADNP 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 ADNP 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 typically begins with chromosomal microarray analysis (CMA). If CMA is not diagnostic, the next step is typically either a multigene panel or exome sequencing. Single-gene testing (sequence analysis of ADNP, followed by gene-targeted deletion/duplication analysis) may be indicated in individuals with the distinctive findings described in Suggestive Findings.

• Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP array to detect genome-wide large deletions/duplications (including ADNP) that cannot be detected by sequence analysis.
• Single-gene testing. Sequence analysis of ADNP can be performed to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
• A multigene panel that includes ADNP and other genes of interest (see Differential Diagnosis) may be considered to identify the genetic cause 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(s) are likely involved. Exome sequencing is most commonly used and yields results similar to a 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.
• Epigenetic signature analysis / methylation array. Two distinctive epigenetic signatures (disorder-specific genome-wide changes in DNA methylation profiles) in peripheral blood leukocytes have been identified in individuals with ADNP-related disorder [Aref-Eshghi et al 2020]. Individuals with an ADNP pathogenic variant located outside the region between nucleotides 2000 and 2340 have a distinct epigenetic signature, whereas individuals with an ADNP pathogenic variant located between nucleotides 2000 and 2340 have a different epigenetic signature [Bend et al 2019, Breen et al 2020]. Epigenetic signature analysis of a peripheral blood sample or DNA banked from a blood sample can therefore be considered to clarify the diagnosis in individuals with clinical findings of ADNP-related disorder and a variant of uncertain clinical significance identified by molecular genetic testing. For an introduction to epigenetic signature analysis click here.

Clinical Description

The following clinical description is based on a published report of a large cohort of 78 individuals in whom a pathogenic variant in ADNP has been identified [Van Dijck et al 2019].

Of note, the oldest individual known to the authors to date is age 40 years [Author, personal observation].

Development. Infants often have hypotonia. Developmental milestones are delayed: the average age to sit independently is 13 months, and the average walking age is 2.5 years. Speech impairment is prominent, with expressive language ranging from no words to sentences. Bladder training is delayed in half of affected individuals.

All have mild-to-severe intellectual disability.

Autism spectrum disorder (ASD), characterized by stereotypic behavior and impaired social interaction, is reported in 67% of the children. Children have a strong sensory interest (sensory processing disorder). A high pain threshold is common.

Additional behavior problems may include anxiety, obsessive compulsive disorder, aggressive behavior, temper tantrums, attention-deficient/hyperactivity disorder, and sleep problems.

Characteristic facial features include a prominent forehead, high anterior hairline, ptosis, downslanted palpebral fissures, prominent eyelashes, wide and depressed nasal bridge, short nose with full, upturned nasal tip, a long philtrum, thin vermilion of the upper lip, widely spaced teeth, pointed chin, and ear abnormalities including small low-set ears and protruding cup-shaped ears.

Gastrointestinal/feeding. Feeding difficulties and gastrointestinal problems are common, including decreased sucking or chewing, gastroesophageal reflux disease, lack of satiation, frequent vomiting, and constipation. Some individuals required a gastrostomy tube.

Vision issues. More than half have visual problems, most commonly hypermetropia or strabismus. Forty-one percent have cortical visual impairment. Ophthalmologic defects are diverse: ectropion, coloboma, congenital cataracts, nystagmus, everted or notched eyelid, or mild ptosis.

Hand abnormalities are present, including clinodactyly, polydactyly, small fifth fingers, fetal fingertip pads, prominent interphalangeal joints and distal phalanges, a single palmar crease, and nail anomalies.

Foot abnormalities include toe malformations, flat feet, and sandal gap.

Additional muscular skeletal features include joint laxity (38%), pectus deformities (22%) such as pectus excavatum, pectus carinatum or narrow thorax, or skull deformity (14%) including plagiocephaly, trigonocephaly, or brachycephaly.

Endocrine manifestations include thyroid hormone problems (15%, mainly hypothyroidism) and/or growth hormone deficiency. Some have signs of early pubertal development.

Growth. Birth weight, length, and occipitofrontal circumference are within the normal range. Several develop truncal obesity. Twenty-three percent of the individuals have short stature (height <-2 SD in individuals reported with age range of 2-23 years). Growth hormone deficiency is present in 11%.

Cardiac anomalies. Atrial septal defect is the most common. Less frequent cardiac defects include: patent ductus arteriosus, patent foramen ovale, mitral valve prolapse, ventricular septal defect, and other cardiovascular malformations.

Seizures. Some children have seizures (16%) including absence seizures, focal seizures with reduced awareness, and epilepsy with continuous spike and waves during slow-wave sleep.

Renal. Renal anomalies include narrow ureters or bilateral vesicoureteral reflux.

Recurrent infections. Most children have recurrent infections, including upper respiratory and urinary tract infections (51%).

Other

• Submucous cleft palate (1 individual)
• Metopic craniosynostosis (2 individuals)

Genotype-Phenotype Correlations

There is no evidence for a clinically relevant impact of a specific pathogenic variant on the clinical presentation. However, it was noticed that individuals with a p.Tyr719Ter pathogenic variant walked later and had a higher pain threshold than those with other ADNP pathogenic variants [Van Dijck et al 2019].

Penetrance

Penetrance is less than 100%; In two families reported to date, probands diagnosed with ADNP-related disorder inherited a pathogenic variant from an unaffected parent [Van Dijck et al 2019].

Prevalence

The prevalence of pathogenic variants in ADNP is estimated at 0.17% of individuals with 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].

Evaluations Following Initial Diagnosis

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

Treatment of Manifestations

Treatment is symptomatic; no specific therapy is available. Routine medical care by a pediatrician or primary care physician is recommended.

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

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 knockout mouse model has not been evaluated for autistic traits, the observations raise hope for treatment in individuals with ADNP-related disorder [Vandeweyer et al 2014].

A Phase II trial with the drug ketamine in children with ADNP-related disorder is currently recruiting.

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

ADNP-related disorder 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 ADNP-related disorder whose parents have undergone molecular genetic testing have the disorder as the result of a de novo ADNP pathogenic variant.
• In two families reported to date, probands diagnosed with ADNP-related disorder inherited a pathogenic variant from an unaffected parent [Van Dijck et al 2019].
• 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, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
  • 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.

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

• If the ADNP 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].
• If a parent of the proband is known to have the ADNP pathogenic variant identified in the proband, the risk to the sibs of inheriting the variant is 50%.

Offspring of a proband

• Each child of an individual with ADNP-related disorder has a 50% chance of inheriting the ADNP pathogenic variant.
• Individuals with ADNP-related syndromic autism are not known to reproduce.

Other family members

• The risk to other family members depends on the genetic status of the proband's parents: if a parent has the ADNP pathogenic variant, the parent's family members may be at risk.
• Given that most probands with ADNP-related disorder 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.

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 the parents of an affected individual.

Prenatal Testing and Preimplantation Genetic Testing

Once the ADNP 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

ADNP contains five exons, the last three of which are translated. The protein contains nine zinc fingers and three other functional domains, including NAP, an 8-amino-acid neuroprotectant peptide (NAPVSIPQ), a DNA-binding homeobox domain, and a HP1-binding motif.

ADNP is a vasoactive intestinal peptide (VIP)-responsive gene. VIP, a neuroprotective peptide, is active during embryonic development, in particular during the time of neuronal tube closure. It protects damaged nerve cells from cell death by inducing glia-derived, survival-promoting substances [Helsmoortel et al 2014].

Wild type ADNP directly binds genomic DNA and mediates the recruitment of the BAF complex through its C-terminal end. The C-terminal end is truncated in all individuals with an ADNP-related disorder. It has been hypothesized that the mutated protein still binds to the DNA, but is no longer capable of recruiting the BAF complex, leading to diminished functionality of the complex as a whole and ultimately to deregulation of several cellular processes [Helsmoortel et al 2014]. ADNP has also been shown to interact with the chromatin-remodeling gene CHD4 [Ostapcuk et al 2018].

Mechanism of disease causation. The mutational mechanism is not known, but it has been hypothesized that the mutated ADNP protein competes with the wild type protein to bind with the BAF complexes (the functional eukaryotic equivalent of the SWI/SNF complex that is involved in the regulation of gene expression in yeast) [Helsmoortel et al 2014].

Author Notes

The research group Cognitive Genetics is part of the research cluster Medical Genetics of the Faculty of Pharmaceutical, Biomedical, and Veterinary Sciences of the University of Antwerp. Our mission is to identify genetic causes of cognitive disorders and to study the molecular defects in order to eventually develop rational therapy.

Acknowledgments

We thank the families with individuals affected by an ADNP pathogenic variant who are participating in our research programs.

Author History

Céline Helsmoortel, MSc; University of Antwerp (2016-2021)
Frank Kooy, PhD (2016-present)
Anke Van Dijck, MD, PhD (2016-present)
Geert Vandeweyer, PhD (2016-present)

Revision History

• 6 October 2022 (sw) Revision: epigenetic signature analysis (Establishing the Diagnosis)
• 15 April 2021 (sw) Comprehensive update posted live
• 7 April 2016 (bp) Review posted live
• 18 December 2015 (avd) Original submission

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