Clinical characteristics.

DLG4-related synaptopathy is characterized by developmental delay, intellectual disability (most commonly in the mild-to-moderate range), and autism spectrum disorder. About half of affected individuals have epilepsy. Regression in motor development and/or language has been reported in about 40% of affected individuals. Other neurologic findings can include hypotonia, movement disorder (most commonly stereotypies and ataxia), dystonia, tremor, and migraine headaches. Sleep disturbance is common, with sleep onset and/or sleep maintenance difficulties being frequently reported. Strabismus is the most common ocular finding followed by hyperopia, nystagmus, and cortical blindness. Vomiting is observed in a number of individuals and can be triggered by seizures, motion sickness, or fatigue. Joint laxity is a relatively common finding (36.9%), and scoliosis is noted in 20% of individuals.

Diagnosis/testing.

The diagnosis of DLG4-related synaptopathy is established in a proband with suggestive clinical findings and a heterozygous pathogenic variant in DLG4 identified by molecular genetic testing.

Management.

Treatment of manifestations: There is no cure for DLG4-related synaptopathy. Supportive care includes standard treatment for developmental delay / intellectual disability, epilepsy, migraine, ataxia, dystonia, refractive errors, strabismus, and cerebral visual impairment. Behavioral therapy may aid those who have insomnia, while pharmacotherapy may be considered in those who have refractory sleep disturbance.

Surveillance: At each visit, monitor those with seizures; assess for new manifestations such as seizures, changes in tone, movement disorders, and migraine headaches; monitor developmental progress and educational needs; assess mobility and self-help skills; and assess for signs/symptoms of sleep disturbance. At each visit after infancy, assess for behavioral issues such as anxiety, autism spectrum disorder, attention-deficit/hyperactivity disorder, aggression, or self-injury. Annually or as clinically indicated, ophthalmology evaluation; and 24-hour EEG in those with significant cognitive/behavioral delay, developmental regression, or abnormal routine EEG.

Genetic counseling.

DLG4-related synaptopathy is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Rarely, individuals diagnosed with DLG4-related synaptopathy inherited a DLG4 pathogenic variant from a heterozygous or mosaic parent. In general, the risk to other family members is presumed to be low. However, once a DLG4 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

DLG4-related synaptopathy should be considered in individuals with the following clinical brain MRI findings and family history.

Clinical findings

• Mild-to-severe developmental delay (DD) or intellectual disability (ID)

AND

• Any of the following features presenting in infancy or childhood:
  • Generalized hypotonia
  • Developmental regression
  • Movement disorder, including stereotypies, ataxia, dystonia, and tremor
  • Generalized or focal epilepsy, with or without epileptic encephalopathy
  • Sleep problems, including issues with sleep onset and/or sleep maintenance
  • Neuropsychiatric/behavioral issues, such as autism spectrum disorder, attention-deficit/hyperactivity disorder, and/or anxiety
  • Ophthalmologic involvement, including strabismus, nystagmus, hyperopia, and cortical blindness
  • Skeletal manifestations, such as joint laxity and scoliosis
  • Gastroenteric disturbances, such as feeding difficulties at birth or in early infancy, gastroesophageal reflux disease, and/or vomiting
  • Nonspecific dysmorphic features (See Clinical Description.)

Brain MRI findings

• Brain or cerebellar atrophy
• Abnormalities of the corpus callosum
• Abnormalities of the hippocampus, including a dysmorphic appearance

Family history. Because DLG4-related synaptopathy 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 autosomal dominant inheritance (e.g., affected males and females in multiple generations).

Establishing the Diagnosis

The diagnosis of DLG4-related synaptopathy is established in a proband with suggestive clinical findings and a heterozygous pathogenic (or likely pathogenic) variant in DLG4 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 DLG4 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 (ID) may begin with a large multigene panel (including all the known ID-related genes at the time of genetic testing) or exome/genome sequencing. Note: Single-gene testing (sequence analysis of DLG4, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• An ID or epilepsy multigene panel that includes DLG4 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. Of note, given the rarity of DLG4-related synaptopathy and how recently it has been described, some panels for ID or epilepsy may not yet include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome or genome 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 prior to testing. Exome sequencing is most commonly used and yields results similar to an ID/epilepsy 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 and has the additional advantage of detecting single or multiexon deletions/duplications and deep intronic variants.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

To date, about 100 individuals have been identified with a pathogenic variant in DLG4 [Rodríguez-Palmero et al 2021; Authors, personal observation]. Information about individuals with larger deletions of 17p13.1 that include DLG4 and adjacent genes is not included in this chapter. The following description of the phenotypic features associated with DLG4-related synaptopathy is based on 53 reported individuals.

Developmental delay (DD) and intellectual disability (ID). DD before age two years is one of the first signs of DLG4-related synaptopathy, although DD may not be appreciated until later in childhood. DD in more than one developmental domain is seen in most individuals. Others may have isolated motor or language delay, with a subset (approximately 20%) being nonverbal. ID is ubiquitous in individuals reported in the literature, with a relatively equal frequency of affected individuals falling into the mild, moderate, and severe ranges. The average age of walking is 20.7 months, and the average age of first words is 32.2 months.

Regression in motor development and/or language has been reported in about 40% of affected individuals. Most of the individuals with language regression (with or without motor regression) had autism spectrum disorder (ASD), but not all the individuals with ASD had language regression.

• Epilepsy can be associated with developmental regression, as about 50% of individuals with epilepsy were reported to have regression, compared to 22% of those without epilepsy.
• Infection may also be another triggering factor for developmental regression.

Other neurologic features

• Hypotonia is observed in about half of affected individuals, while spasticity has only been observed in a few individuals.
• Movement disorders, most commonly stereotypies and ataxia, develop in about half of affected individuals, often becoming apparent in childhood. Dystonia and tremor are also observed in some affected individuals.
• Migraine headache is reported by several parents and may be an underdiagnosed feature.

Epilepsy. About 50% of affected individuals have epilepsy.

• Both generalized and focal seizures have been described, although focal seizures are more common.
• Febrile seizures, infantile spasms, and electrical status epilepticus in sleep (ESES) have also been observed [Tassinari & Rubboli 2019].
• The mean age of onset of the first seizure is six years (range: 6 months to 15 years).
• EEG may show focal abnormalities (which may be multifocal), an abnormal background, or, less frequently, generalized abnormalities.

Neuropsychiatric/behavioral issues

• ASD is reported in 56% of affected individuals and is more often diagnosed in those with moderate-to-severe ID than in those with mild ID. ASD is also common in individuals with language regression, but not all those with ASD have language regression.
• Attention-deficit/hyperactivity disorder (ADHD) is reported in 57% of affected individuals and tends to occur more frequently in those with a co-occurring ASD diagnosis.
• Anxiety, which can be triggered by different factors such as sound or separation, is reported in about 50% of affected individuals and may be present starting in childhood.

Sleep disturbances are common, with sleep onset and/or sleep maintenance difficulties being frequently reported.

• Circadian rhythm abnormalities, including advanced sleep-wake phase, have also been seen.
• The sleep disturbances may overlap with nocturnal epilepsy.

Growth. Prenatal and postnatal growth is typically in the normal range for weight, length/height, and head circumference.

Ophthalmologic. Strabismus is the most common ocular finding, followed by hyperopia, nystagmus, and cortical blindness. Myopia, amblyopia, and slow upgaze are also seen but less frequently.

Neuroimaging. Thirty percent of individuals who have undergone neuroimaging have abnormalities, including atrophy of the cerebrum/cerebellum, thinning of the corpus callosum, and a dysmorphic appearance (abnormal morphology) of the hippocampus. Abnormal imaging is more common in individuals with moderate or severe ID.

Other associated features

• Gastrointestinal issues. Vomiting is observed in a number of individuals and can be triggered by seizures, motion sickness, or fatigue.
• Musculoskeletal features. Joint laxity is a relatively common finding (36%), and scoliosis is noted in 20% of individuals. Marfanoid habitus (long face, slender body habitus, pectus excavatum, and/or long and thin fingers) has been noted in some individuals.
• Facial features. No specific dysmorphic features have been observed. If present, dysmorphic features are nonspecific.

Prognosis. Life expectancy in DLG4-related synaptopathy is unknown. One reported individual is alive at age 47 years [Rodríguez-Palmero et al 2021], demonstrating that survival into adulthood occurs. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that this condition is often unrecognized, and thus underreported, in adults.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Nomenclature

This condition is sometimes referred to by the acronym SHINE (sleep disturbances, hypotonia, intellectual disability, neurologic disorder, and epilepsy).

Prevalence

DLG4-related synaptopathy is rare, but its exact prevalence is unknown. Only 53 individuals with pathogenic DLG4 variants have been published [Rodríguez-Palmero et al 2021]. However, through collaborations with the SHINE Syndrome Foundation (see Resources), approximately 100 individuals diagnosed with a pathogenic DLG4 variant have been identified.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with DLG4-related synaptopathy, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

There is no cure for DLG4-related synaptopathy.

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Evaluation of Relatives at Risk

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

Pregnancy Management

Although there has not as yet been documentation of a pregnancy in a person with DLG4-related synaptopathy, it is possible for those who are mildly affected.

In general, women with DLG4-related synaptopathy who have epilepsy or seizures are at greater risk for mortality during pregnancy than pregnant women without seizures; use of anti-seizure medication (ASM) during pregnancy reduces this risk. However, exposure to ASM may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which the medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from ASM exposure is often less than that associated with exposure to untreated maternal seizures. Therefore, ASM to treat maternal seizures during pregnancy is typically recommended. Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [Sarma et al 2016].

See MotherToBaby for further information on medication use during pregnancy.

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

DLG4-related synaptopathy 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 DLG4-related synaptopathy whose parents have undergone molecular genetic testing have the disorder as the result of a de novo DLG4 pathogenic variant.
• Rarely, individuals diagnosed with DLG4-related synaptopathy inherited a DLG4 pathogenic variant from a parent with somatic mosaicism or parents with suspected germline mosaicism [Rodríguez-Palmero et al 2021].
• 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 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 [Rodríguez-Palmero et al 2021]. 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:

• If a parent of the proband is known to have the DLG4 pathogenic variant identified in the proband, the risk to the sibs of inheriting the variant is 50%.
• If the DLG4 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is only slightly greater than that of the general population because of the possibility of parental germline mosaicism [Rodríguez-Palmero et al 2021].

Offspring of a proband. Each child of an individual with DLG4-related synaptopathy has a 50% chance of inheriting the DLG4 pathogenic variant.

Other family members. Given that most probands with DLG4-related synaptopathy reported to date have the disorder as the result of a de novo DLG4 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

Once the DLG4 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

DLG4 encodes disks large homolog 4 (DLG4), also called postsynaptic density protein 95 (PSD-95), which plays a crucial role in the postsynaptic region of excitatory (glutamatergic) neurons, as it organizes the key components of the postsynaptic density essential for synaptic signaling, development, and survival. DLG4 contains three PDZ domains, a SH3 domain, and a GK domain. DLG4 interacts directly or indirectly with several proteins, including glutamate receptors (such as NMDA and AMPA receptors), ion channels (such as Shaker type K⁺ channels), cell adhesion molecules (such as neuroligin), transmembrane proteins (such as ADAM22), and SYNGAP1, which are also involved in neurodevelopmental disorders with or without epilepsy. The overlapping symptoms observed in DLG4-related synaptopathy and other neurodevelopmental disorders suggest that pathogenic variants in DLG4 likely disrupt the normal function of glutamatergic synapses during development and later in life, either directly or indirectly by affecting the normal function of DLG4 interaction partners [Levy et al 2022].

Mechanism of disease causation. Most reported disease-causing DLG4 variants are protein truncating and predicted to be loss of function (LoF) variants.

There are also a few heterozygous likely pathogenic DLG4 missense variants that may also be LoF variants, but this hypothesis has yet to be proven [Levy et al 2022]. Furthermore, a silent variant was shown to affect RNA splicing and predicted to be a LoF variant [Rodríguez-Palmero et al 2021]. Further, for variants where RNA escapes nonsense-mediated decay, a dominant-negative effect cannot be excluded.

DLG4-specific laboratory technical considerations: gene annotation. DLG4 variants are in general annotated using one of the following transcripts:

• NM_001321075.3 consists of 20 exons and encodes the alpha isoform of 724 amino acids (NP_001308004.1). This isoform is the major isoform expressed in the brain.
• NM_001365.4 consists of 22 exons and encodes the beta isoform of 767 amino acids (NP_001356.1).

The main difference between these two transcripts is the presence of two extra exons at the 5' end of the gene in the longer transcript (NM_001365.4).

In case of synonymous or deep intronic variants that are predicted to affect splicing by in silico tools, RNA testing (RT-PCR or RNA sequencing) could be considered to establish the pathogenicity of the variant. This can be successfully performed using peripheral blood, as the gene is expressed in low levels in this tissue [Z Tümer, personal communication].

Author Notes

Zeynep Tümer, kd.hnoiger@remut.penyez

• Clinical work: genetic diagnosis of neurodevelopmental disorders and congenital imprinting disorders
• Research interests: understanding the underlying molecular mechanisms involved in monogenic and complex neurodevelopmental disorders
• Web page: www.rigshospitalet.dk

Thomas J Dye, gro.cmhcc@eyd.samoht

• Clinical work: pediatric sleep medicine, neurodevelopmental disorders, sleep-related movement disorders and epilepsy
• Research interests: understanding sleep and circadian disruption of neurodevelopmental disorders
• Web page: www.cincinnatichildrens.org

Carlos Prada, gro.snerdlihceirul@adarpc

• Clinical work: neurofibromatosis, RASopathies, lysosomal storage disorders, metabolic disorders, and implementation of genomics in clinical care
• Research interests: development of biomarkers for rare diseases, clinical trials, and gene discovery
• Web page: www.luriechildrens.org

Alexandre White-Brown, ac.no.oehc@nworbetihwa

• Research interests: development of strategies to improve the diagnostic care of individuals with rare genetic disease; exploring the use of artificial intelligence to identify patients with undiagnosed rare genetic diseases

Alex MacKenzie, oc.no.oehc@eizneKcaM

• Clinical work: general pediatrician
• Research interests: therapies for rare neurogenetic disorders
• Web page: www.cheoresearch.ca

Amanda Levy, kd.hnoiger@yvel.tsub.adnama.eiram

• Research interests: understanding the genetic and functional mechanisms of rare neurodevelopmental disorders

Acknowledgments

The patient support group SHINE Syndrome Foundation is acknowledged for collaboration and their contribution to understanding the phenotype and genotype of the condition. The board members of the foundation have also made invaluable suggestions to the chapter.

Revision History

• 22 June 2023 (ma) Review posted live
• 5 December 2022 (zt) Original submission

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