Clinical Guidance

No genotype-phenotype correlations have been identified to date. Significant phenotypic variability has been observed both between individuals from different families with a recurrent variant and among individuals from a single family who have the same variant . The phenotypes of males with haploinsufficiency (due to exon deletions or frameshift or nonsense variants) were noted to be relatively milder than the phenotypes of individuals with missense variants .

Source: GeneReviews — "CLCN4-Related Neurodevelopmental Disorder"

Diagnostic Criteria

No consensus clinical diagnostic criteria for CLCN4-related neurodevelopmental disorder have been published.

Suggestive Findings

CLCN4-related neurodevelopmental disorder (CLCN4-NDD) should be considered in individuals with the following clinical and brain MRI findings and family history.

Clinical findings

• Developmental delay or intellectual disability

• Autism spectrum disorder

• Epilepsy

• Mental health conditions including anxiety and bipolar disorder

• Gastrointestinal dysfunction

• Unremarkable facial features. Although a subtle lengthening of the face and squaring of the chin that becomes more prominent with age has been noted in several individuals (see Figure 3 in ; full text), these features are not likely to be distinctive enough to trigger consideration of this specific diagnosis.

Source: GeneReviews — "CLCN4-Related Neurodevelopmental Disorder"

Differential Diagnosis

Because the phenotypic features associated with CLCN4-related neurodevelopmental disorder are not sufficient to diagnose this condition, all disorders with intellectual disability, autism spectrum disorder, and epilepsy without other distinctive findings should be considered in the differential diagnosis. See OMIM Phenotypic Series:

• Autosomal Dominant Intellectual Developmental Disorder

• Autosomal Recessive Intellectual Developmental Disorder

• Nonsyndromic X-Linked Intellectual Developmental Disorder

• Syndromic X-Linked Intellectual Developmental Disorder

• Developmental and Epileptic Encephalopathy

• Idiopathic Generalized Epilepsy

• Susceptibility to Autism

Source: GeneReviews — "CLCN4-Related Neurodevelopmental Disorder"

Management Guidelines

No consensus clinical practice guidelines for CLCN4-related neurodevelopmental disorder have been published; the following management recommendations are based on review of the literature [, , , , , , ] and the authors' personal observations. Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with CLCN4-related neurodevelopmental disorder (CLCN4-NDD), the evaluations summarized (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 CLCN4-Related Neurodevelopmental Disorder

Source: GeneReviews — "CLCN4-Related Neurodevelopmental Disorder"

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.

Source: GeneReviews — "CLCN4-Related Neurodevelopmental Disorder"

Surveillance Guidelines

Table 5. Recommended Surveillance for Individuals with CLCN4-Related Neurodevelopmental Disorder

Source: GeneReviews — "CLCN4-Related Neurodevelopmental Disorder"