Radio-Tartaglia Syndrome in Males, Clinical Data Indicate a Relatively Mild Phenotype with Predominantly Psychiatric Symptoms
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction:
Radio-Tartaglia syndrome (RATARS) (MIM#619312) is a neurodevelopmental disorder caused by heterozygous truncating variants in SPEN on chromosome 1p36. About 34 individuals, predominantly females, have been described. RATARS in females is characterized by developmental motor and speech delay, hypotonia, and severe intellectual disability. The phenotypic spectrum in males is unknown.
Methods:
In our in-house database of over 60,000 exomes, we utilized sequence data to improve genotype phenotype correlation in RATARS. Individuals were referred for clinical evaluation and diagnostic testing. Clinical data and DNA specimens were collected and used after signed informed consent. Genomic analyses were performed with DNA samples obtained from leukocytes. ES data processing, sequence alignment to GRCh37/GRCh38, and variant filtering and prioritization by allele frequency, predicted functional impact, and inheritance were performed as previously reported for our diagnostic pipeline.
Results:
We identified 5 males with RATARS ranging in age from 2 yrs to 45 yrs, in 2 incidences the variants were sporadic, and in 3 males the variant was familial. In the familial case the pathogenic variant in two boys was inherited from the affected father. The main clinical features were borderline low IQ, learning disability, speech delay, autism spectrum disorder (ASD), aggressive behavior, impulse control deficits and behavioral dysregulation.
Conclusion:
In males, RATARS appears to present with a milder phenotype than described in females. Reproduction is possible, and therefore, RATARS should be considered in the differential diagnoses of ASD and other behavioral disorders, especially when transmitted through the paternal lineage. Our approach indicates the usefulness of phenotypic information in diagnostic databases to extend the phenotypic spectrum and to improve genotype phenotype correlations in rare disorders.
Radio-Tartaglia syndrome (RATARS) (MIM#619312) is a neurodevelopmental disorder caused by heterozygous truncating variants in SPEN on chromosome 1p36. About 34 individuals, predominantly females, have been described. RATARS in females is characterized by developmental motor and speech delay, hypotonia, and severe intellectual disability. The phenotypic spectrum in males is unknown.
Methods:
In our in-house database of over 60,000 exomes, we utilized sequence data to improve genotype phenotype correlation in RATARS. Individuals were referred for clinical evaluation and diagnostic testing. Clinical data and DNA specimens were collected and used after signed informed consent. Genomic analyses were performed with DNA samples obtained from leukocytes. ES data processing, sequence alignment to GRCh37/GRCh38, and variant filtering and prioritization by allele frequency, predicted functional impact, and inheritance were performed as previously reported for our diagnostic pipeline.
Results:
We identified 5 males with RATARS ranging in age from 2 yrs to 45 yrs, in 2 incidences the variants were sporadic, and in 3 males the variant was familial. In the familial case the pathogenic variant in two boys was inherited from the affected father. The main clinical features were borderline low IQ, learning disability, speech delay, autism spectrum disorder (ASD), aggressive behavior, impulse control deficits and behavioral dysregulation.
Conclusion:
In males, RATARS appears to present with a milder phenotype than described in females. Reproduction is possible, and therefore, RATARS should be considered in the differential diagnoses of ASD and other behavioral disorders, especially when transmitted through the paternal lineage. Our approach indicates the usefulness of phenotypic information in diagnostic databases to extend the phenotypic spectrum and to improve genotype phenotype correlations in rare disorders.