Clinical characteristics.

DYRK1A syndrome is characterized by intellectual disability including impaired speech development, autism spectrum disorder including anxious and/or stereotypic behavior problems, and microcephaly. Affected individuals often have a clinically recognizable phenotype including a typical facial gestalt, feeding problems, seizures, hypertonia, gait disturbances, and foot anomalies. The majority of affected individuals function in the moderate-to-severe range of intellectual disability; however, individuals with mild intellectual disability have also been reported. Other medical concerns relate to febrile seizures in infancy; the development of epilepsy with seizures of the atonic, absence, and generalized myoclonic types; short stature; and gastrointestinal problems. Ophthalmologic, urogenital, cardiac, and/or dental anomalies have been reported.

Diagnosis/testing.

The diagnosis of DYRK1A syndrome is established in a proband with suggestive findings and a heterozygous pathogenic variant in DYRK1A identified by molecular genetic testing.

Management.

Treatment of manifestations: Educational and therapy programs to address the specific needs identified; routine treatment of epilepsy under the care of a neurologist; standard treatment for orthopedic, dental, cardiac, urogenital, ophthalmologic, constipation, and other medical issues.

Surveillance: Regular monitoring and guidance for educational and behavior problems, growth parameters and nutritional status, and safety of oral intake; regular lifelong follow up as determined by specialists for issues present affecting heart, eyes, and teeth.

Genetic counseling.

DYRK1A syndrome is an autosomal dominant disorder typically caused by a de novo pathogenic variant. If the DYRK1A pathogenic variant identified in the proband is not identified in either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism. Once the DYRK1A pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

DYRK1A syndrome should be considered in individuals with mild-to-severe psychomotor developmental delay (DD) or intellectual disability (ID) AND any of the following additional features presenting in infancy or childhood:

• Intrauterine growth retardation
• Microcephaly
• Typical facial gestalt:
  • During infancy and childhood facial features include prominent ears, deep-set eyes, mild upslanted palpebral fissures, a short nose with a broad nasal tip, and retrognathia with a broad chin.
  • In adulthood, the nasal bridge may become high and the alae nasi underdeveloped, giving the nose a more prominent appearance [van Bon et al 2016].
• Neonatal feeding difficulties that may persist
• Epilepsy (febrile seizures, atonic seizures, absence seizures, and generalized myoclonic seizures)
• Hypertonia
• Abnormal gait
• Behavioral problems such as autism spectrum disorder, anxiety, and/or sleep disturbances
• Foot anomalies: mild cutaneous syndactyly of toes 2-4; hallux valgus; and short fifth toe
• Vision abnormalities (strabismus, myopia, hypermetropia, retinal anomalies, optic atrophy, coloboma)
• Urogenital anomalies (undescended testes, hypoplastic scrotum, micropenis, inguinal hernia, renal abnormalities)

Establishing the Diagnosis

The diagnosis of DYRK1A syndrome is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in DYRK1A identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG 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. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous DYRK1A variant of uncertain significance does not establish or rule out the diagnosis of this disorder.

Molecular genetic testing in a child with developmental delay or an older individual with intellectual disability typically begins with chromosomal microarray analysis (CMA). If CMA is not diagnostic, the next step is typically either a multigene panel or exome sequencing. Note: Single-gene testing (sequence analysis of DYRK1A, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including DYRK1A) that cannot be detected by sequence analysis.
• An intellectual disability (ID) multigene panel that includes DYRK1A and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition in a person with a nondiagnostic CMA while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used and yields results similar to an ID multigene panel with the additional advantage that exome sequencing includes genes recently identified as causing ID, whereas some multigene panels may not.
  Genome sequencing is also possible.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

DYRK1A syndrome is characterized by intellectual disability including impaired speech development, autism spectrum disorder with anxious and/or stereotypic behavior problems, and microcephaly. Affected individuals often have a clinically recognizable phenotype including a typical facial gestalt, feeding problems, seizures, hypertonia, gait disturbances, and foot anomalies [van Bon et al 2016].

To date, 68 individuals have been reported with a pathogenic variant in DYRK1A [Møller et al 2008, van Bon et al 2011, Courcet et al 2012, O'Roak et al 2012, Redin et al 2014, Bronicki et al 2015, Ji et al 2015, Ruaud et al 2015, Luco et al 2016, van Bon et al 2016, Earl et al 2017, Evers et al 2017, Murray et al 2017, Blackburn et al 2019, Qiao et al 2019, Lee et al 2020]. The following description of the phenotypic features associated with this condition is based on these reports.

Developmental delay (DD) and intellectual disability (ID). Generalized hypertonia may already be noted during the first months of life. Motor development is often impaired by gait disturbances and hypertonia.

• Although some individuals achieve independent walking at the upper age limit of normal, the majority achieve walking after age two to three years.
• The majority are described as having a broad-based/ataxic gait [Ji et al 2015, van Bon et al 2016]. A more detailed report describes a lilting gait with forward lean to the upper body, arms bent and held tight against the body, and hands splayed [Earl et al 2017].

All individuals show delayed development of speech. Some individuals learn to speak; others show a lack of speech or the use of one- to two-word utterances only. In general, expressive language is more severely affected than receptive language.

The majority of affected individuals function in the moderate-to-severe range of intellectual disability; however, individuals with mild intellectual disability have also been reported.

Other neurodevelopmental features

• Abnormal tone. Generalized hypertonia may already be noted during the first months of life.
• Feeding problems due to difficulties with suck and swallowing and gastrointestinal reflux occur in the majority of infants. Feeding problems may persist during childhood and adulthood, warranting tube feeding in some affected individuals [van Bon et al 2016].

Epilepsy. Febrile seizures during infancy are common. About 50% of affected individuals develop epilepsy including seizures of the atonic, absence, and generalized myoclonic types [Courcet et al 2012, Bronicki et al 2015, Ji et al 2015, van Bon et al 2016].

Behavior problems. Autism spectrum disorders, stereotypies, anxious behavior, hyperactivity, and sleep disturbances (difficulty falling asleep, awakening at night) have been observed [van Bon et al 2016, Earl et al 2017]. In almost half of affected individuals an official ASD diagnosis has been reported. However, this percentage increases to almost 70% when broadening the criteria to include ASD-related behaviors without a formal diagnosis [Earl et al 2017].

Growth

• Microcephaly, intrauterine growth restriction, and/or oligohydramnios may be noted prenatally. Head circumference at birth is between −1 and −4 SD and abnormally slow head growth causes the deviation to further increase over time to −2 to −5 SD in the majority (95%) of individuals. Low birth weight (<−2 SD) has also frequently been reported.
• Low weight and a slender build later in life are also common [Courcet et al 2012, Deciphering Developmental Disorders Study Group 2015, Ruaud et al 2015, van Bon et al 2016]. Only four individuals have been reported with a weight above the 50th percentile [Bronicki et al 2015, Luco et al 2016, van Bon et al 2016].
• Short stature (<−2 SD) has been reported in about 44% of individuals. Onset may occur prior to birth or later in childhood. A height above the 50th percentile has been reported in two individuals [Bronicki et al 2015, Ji et al 2015, van Bon et al 2016, Evers et al 2017].

Sensory impairment. Eye abnormalities are common and typically include strabismus, astigmatism, and hypermetropia. However, iris coloboma, optic nerve dysfunction, corneal clouding, early cataract, and retinal detachment have also been reported [Bronicki et al 2015, Ji et al 2015, van Bon et al 2016, Earl et al 2017].

Neuroimaging. Brain imaging may show findings indicative of global cerebral underdevelopment or hypomyelination. It may detect enlarged ventricles, myelination delay, cortical brain atrophy, hypoplasia of the corpus callosum, a small brain stem, and/or a hypoplastic pituitary stalk [Bronicki et al 2015, Ji et al 2015, van Bon et al 2016, Evers et al 2017].

Other associated features

• Facial features. During infancy and childhood facial features include prominent ears, deep-set eyes, mild upslanted palpebral fissures, a short nose with a broad nasal tip, and retrognathia with a broad chin. In adulthood, the nasal bridge may become high and the alae nasi underdeveloped, giving the nose a more prominent appearance [van Bon et al 2016].
• Cardiac defects include atrial septum defect, ventricular septum defect, hypoplastic left heart, aortic valve and pulmonary valve abnormalities, aortic stenosis, and patent ductus arteriosus.
• Gastrointestinal problems mainly include gastrointestinal reflux and (sometimes severe) constipation.
• Urogenital anomalies may include undescended testes, hypoplastic scrotum, shawl scrotum, micropenis, hypospadias, inguinal hernia, frequent urinary infections, vesicoureteral reflux, and unilateral renal agenesis.
• Musculoskeletal features. In about 10% of affected individuals scoliosis, kyphosis, and/or pectus excavatum has been reported. Several individuals show a typical foot anomaly: a combination of mild cutaneous syndactyly of toes 2-4, hallux valgus, and a short fifth toe has been noted in several individuals [van Bon et al 2016].
• Dental anomalies including widely spaced teeth, extreme calculus (hardened dental plaque), delayed primary dentition, neonatal teeth, and supernumerary teeth have also been reported.

Prognosis. Based on current data, life span is not limited by this condition as several adult individuals have been reported. Data on possible progression of behavior abnormalities or neurologic findings are still limited.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Penetrance

Penetrance is likely to be 100% in individuals with a de novo pathogenic variant. Haploinsufficiency of DYRK1A has not been observed in control populations. Expressivity is similar in males and females [van Bon et al 2016].

Prevalence

Studies have demonstrated that DYRK1A syndrome accounts for 0.1%-0.5% of individuals with intellectual disability and/or autism [Courcet et al 2012, O'Roak et al 2012, Deciphering Developmental Disorders Study Group 2015, van Bon et al 2016].

Evaluations Following Initial Diagnosis

To establish the extent of the disease and needs in an individual diagnosed with DYRK1A syndrome, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

Standard treatment is recommended for orthopedic, dental, cardiac, urogenital, ophthalmologic, constipation, and other medical issues.

Surveillance

Regular lifelong follow up as determined by specialists for issues present affecting heart, eyes, and teeth is recommended.

Evaluation of Relatives at Risk

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

Therapies Under Investigation

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. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

DYRK1A syndrome is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• All probands reported to date with DYRK1A syndrome whose parents have undergone molecular genetic testing have the disorder as the result of a de novo DYRK1A pathogenic variant.
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent, 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 and will not detect a pathogenic variant that is present in the germ cells only.

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

• To date, all individuals with DYRK1A syndrome whose parents have undergone molecular genetic testing have had a de novo pathogenic variant, suggesting a low risk to sibs.
• If the DYRK1A 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 DYRK1A pathogenic variant identified in the proband, the risk to the sibs of inheriting the variant is 50%.

Offspring of a proband. To date, individuals with DYRK1A syndrome are not known to reproduce. The risk to offspring of an affected individual of inheriting the variant is 50%.

Other family members. Given that, to date, all reported probands with DYRK1A syndrome whose parents have undergone molecular genetic testing have the disorder as a result of a de novo DYRK1A pathogenic variant, the risk to other family members is presumed to be low.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Risk to future pregnancies is presumed to be low, as the proband most likely has a de novo DYRK1A pathogenic variant. There is, however, a recurrence risk (~1%) to sibs based on the theoretic possibility of parental germline mosaicism [Rahbari et al 2016]. Given this risk, prenatal and preimplantation genetic testing may be considered.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

DYRK1A encodes the dual-specificity tyrosine phosphorylation-regulated kinase 1A, a highly conserved protein that plays an essential role in the development of the central nervous system. The protein is a regulator of brain growth and function, including neurogenesis, neuronal proliferation and differentiation, synaptic transmission, and neurodegeneration.

DYRK1A syndrome is caused by haploinsufficiency of the DYRK1A protein product. Heterozygous DYRK1A loss-of-function pathogenic variants include disruptive balanced translocation, deletion, and truncating sequence variants.

Several missense pathogenic variants have also been identified; most are located in the kinase domain, clustering in the proximity of the ATP binding pocket and the catalytic center. These pathogenic variants affect the catalytic domain, leading to abolishment of kinase activity [Widowati et al 2018].

Mechanism of disease causation. Haploinsufficiency resulting from inactivation of one DYRK1A allele

Acknowledgments

The authors would like to thank all individuals with DYRK1A syndrome and their families for sharing their medical and personal stories at the DYRK1A expertise clinic and at (inter)national meetings. They are the true experts, and based upon their knowledge we have been able write this GeneReview chapter.

Revision History

• 18 March 2021 (ha) Comprehensive update posted live
• 17 December 2015 (me) Review posted live
• 31 March 2015 (bvb) Original submission

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