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ADNP-Related Disorder

Synonyms: Helsmoortel-Van der Aa Syndrome, ADNP-Related ID/ASD

, MD, PhD, , PhD, and , PhD.

Author Information

Initial Posting: ; Last Update: April 15, 2021.

Estimated reading time: 17 minutes

Summary

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.

Diagnosis

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.

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 variant in ADNP identified by molecular genetic testing (see Table 1).

Note: Identification of a heterozygous ADNP variant of uncertain significance does not establish or rule out this 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 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. 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.

Table 1.

Molecular Genetic Testing Used in ADNP-Related Disorder

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
ADNP Sequence analysis 399% 4
Gene-targeted deletion/duplication analysis 5None reported
CMA 61 individual 7
1.
2.

See Molecular Genetics for information on variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or 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.
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.

6.

Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including ADNP) that cannot be detected by sequence analysis. The ability to determine the size of the deletion/duplication depends on the type of microarray used and the density of probes in the 20q13.13 region. CMA designs in current clinical use target the 20q13.13 region.

7.

One individual with a heterozygous 20q13.13 deletion that encompassed ADNP and DPM1 presented with features consistent with ADNP-related disorder [Huynh et al 2018].

Clinical Characteristics

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].

Table 2.

Select Features of ADNP-Related Disorder

Feature% of Persons with FeatureComment
DD/ID100%Mild (in 12%), moderate (36%), or severe (52%) ID; ASD & other behavior disorders are common.
Characteristic facial features97%Prominent forehead, high anterior hairline, downslanted palpebral fissures, prominent eyelashes, ear malformations, wide & depressed nasal bridge, short nose w/full, upturned nasal tip, long philtrum, thin upper lip, pointed chin, widely spaced teeth
Gastrointestinal/
feeding issues
83%Gastroesophageal reflux disease, constipation, oral movement problems, lack of satiation, swallowing problems, frequent vomiting
Vision issues74%Strabismus, cortical visual impairment, hypermetropia, ptosis, nystagmus, myopia
Hand & foot abnormalities62%Digit abnormalities, single palmar crease, nail anomalies, sandal gap
Musculoskeletal features55%Joint hypermobility, scoliosis, hip problems, pectus deformities, skull deformities
Endocrine issues25%Early puberty, thyroid hormone problems, growth hormone deficiency
Short stature23%<‒2 SD
Truncal obesity8%
Congenital heart anomalies38%Atrial septal defect, patent ductus arteriosus, mitral valve prolapse, patent foramen ovale, ventricular septal defect
Hearing loss32%Narrow auditory canal, frequent otitis media, hearing loss
Seizures16%Absence seizures, focal seizures w/reduced awareness, epilepsy w/continuous spike & waves during slow-wave sleep
Urinary tract anomalies13%Narrow ureters, bilateral vesicoureteral reflux

ASD = autism spectrum disorder; DD = developmental delay; ID = intellectual disability

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].

Differential Diagnosis

Phenotypic features associated with ADNP pathogenic variants are not sufficient to diagnose ADNP-related disorder. All genes known to be associated with intellectual disability * (ID) should be included in the differential diagnosis of ADNP-related disorder.

* More than 200 have been identified; see OMIM Phenotypic Series: ID, autosomal dominant, ID, autosomal recessive, ID, nonsyndromic, X-linked, and ID, X-linked syndromic)

Management

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.

Table 3.

Recommended Evaluations Following Initial Diagnosis in Individuals with ADNP-Related Disorder

System/ConcernEvaluationComment
Development Comprehensive developmental assessmentTo incl: motor, adaptive, cognitive, & speech/language eval; testing for ASD & ID; eval for early intervention / special education
Psychiatric/
Behavioral
Neuropsychiatric eval if behavioral problems are presentFor persons age >12 mos: screen for behavior concerns incl sleep disturbances, ADHD, anxiety, &/or traits suggestive of ASD.
Gastrointestinal/
Feeding
Gastroenterology / nutrition / feeding team eval
  • To incl eval of aspiration risk & nutritional status
  • Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk.
Vision Ophthalmologic exam & vision assessmentIncl electrophysiologic & visual perception exam to detect cortical visual impairment
Musculoskeletal Orthopedics / physical medicine & rehab / PT / OT evalTo incl assessment of:
  • Gross motor & fine motor skills
  • Joint hypermobility
  • Mobility, activities of daily living, & need for adaptive devices
  • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Growth Measurement of growth parametersTo evaluate for growth deficiency, short stature, obesity
Endocrine Assess for:
  • Thyroid problems;
  • Growth hormone deficiency in those w/short stature.
Cardiac Echocardiogram
Hearing Audiology eval; referral to ENT if indicated
Neurologic Neurologic exam
  • Consider EEG if seizures a concern.
  • To incl brain MRI to detect brain abnormalities
Urinary tract Assess for frequent urinary tract infections
Immunology Assess for recurrent infections
Genetic
counseling
By genetics professionals 1To inform affected persons & their families re nature, MOI, & implications of ADNP-related disorder in order to facilitate medical & personal decision making
Family support/
resources
Assess:

ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; ENT = ear, nose, and throat specialist; ID = intellectual disability; MOI= mode of inheritance; OT = occupational therapy; PT = physical therapy.

1.

Medical geneticist, certified genetic counselor, certified advanced genetic nurse

Treatment of Manifestations

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

Table 4.

Treatment of Manifestations in Individuals with ADNP-Related Disorder

Manifestation/ConcernTreatmentConsiderations/Other
Development Speech, OT, PT; specialized learning programs depending on individual needs
Psychiatric/
Behavioral
Treatment of any neuropsychiatric features incl sleep disorders, &/or behavioral problems
Poor weight gain /
Failure to thrive
Nutritional support if needed
Gastrointestinal Standard treatment for constipation & gastrointestinal reflux
Abnormal vision &/or
strabismus
Standard treatment(s) as recommended by ophthalmologistCommunity vision services through early intervention or school district
Central visual impairment No specific treatment; early intervention to stimulate visual development
Plagiocephaly / Other
musculoskeletal issues
Standard treatment
Hypothyroidism Standard treatment
Cardiac anomalies Standard treatment(s) as recommended by cardiologist
Hearing loss Standard treatments
Seizures Standardized treatment w/AEDs by experienced neurologist
  • Many AEDs may be effective; no one AED has been demonstrated effective specifically for this disorder.
  • Education of parents/caregivers 1
Urinary tract anomalies Standard treatment
Recurrent infections Standard treatment
Family/Community
  • Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
  • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
  • Ongoing assessment of need for palliative care involvement &/or home nursing
  • Consider involvement in adaptive sports or Special Olympics.

AED = antiepileptic drug; OT = occupational therapy; PT = physical therapy

1.

Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.

Surveillance

Table 5.

Recommended Surveillance for Individuals with ADNP-Related Disorder

Manifestation/ConcernTreatmentFrequency
Feeding
  • Measurement of growth parameters
  • Eval of nutritional status & safety of oral intake
At each visit
Musculoskeletal Physical medicine, OT/PT assessment of mobility, self-help skills
Neurologic
  • Monitor those w/seizures as clinically indicated.
  • Assess for new manifestations (e.g., seizures, changes in tone, movement disorders).
Development Monitor developmental progress & educational needs.
Psychiatric/Behavioral Behavioral assessment for anxiety, attention, & aggressive or self-injurious behavior
Eyes Visual assessmentAnnually
Gastrointestinal Monitor for constipation & signs/symptoms of gastrointestinal reflux.At each visit
Family/Community Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources) & care coordination.

OT = occupational therapy; PT = physical therapy

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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

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:

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, his or her 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.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

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.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

ADNP-Related Disorder: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
ADNP 20q13​.13 Activity-dependent neuroprotector homeobox protein ADNP database ADNP ADNP

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for ADNP-Related Disorder (View All in OMIM)

611386ACTIVITY-DEPENDENT NEUROPROTECTOR HOMEOBOX; ADNP
615873HELSMOORTEL-VAN DER AA SYNDROME; HVDAS

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].

Table 6.

Notable ADNP Pathogenic Variants

Reference SequencesDNA Nucleotide ChangePredicted
Protein Change
Comment [Reference]
NM_015339​.5
NP_056154​.1
c.2157C>Gp.Tyr719TerPathogenic variant in exon 4; assoc w/later onset of walking & higher pain threshold than other ADNP pathogenic variants [Van Dijck et al 2019]
c.2491_2494delTTAAp.Leu831IlefsTer82All other pathogenic variants are heterozygous frameshift or nonsense variants in the 3′ end of 5th (last) exon of ADNP & predict a premature termination [Helsmoortel et al 2014].
c.2496_2499delTAAAp.Asn832LysfsTer81
c.2188C>Tp.Arg730TerCommon pathogenic variant

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Chapter Notes

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

  • 15 April 2021 (sw) Comprehensive update posted live
  • 7 April 2016 (bp) Review posted live
  • 18 December 2015 (avd) Original submission

References

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