New Familial Variant Identified in CSDE1-Associated Neurodevelopmental Disorder
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical-Adult
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Secondary Categories:
- Clinical-Adult & Pediatric
Introduction
The CSDE1 gene, also known as UNR, encodes an RNA-binding protein with a cold-shock domain that plays a role in translational reprogramming and is integral to many cellular processes, including cell cycle regulation, apoptosis, neuronal migration and differentiation, and dosage compensation. Most reported variants in CSDE1 are thought to result in loss of function; although many of these variants are de novo, inheritance from a mildly affected parent has also been documented.
Pathogenic or likely pathogenic variants in CSDE1 show incomplete penetrance and variable expressivity. Heterozygous variants in CSDE1 are associated with an autism spectrum and neurodevelopmental disorder phenotype, presenting with a range of neurodevelopmental symptoms from mild to severe intellectual disability, as well as delays in speech and motor development. Additional features observed in some affected individuals include sleep disturbances, seizures, macrocephaly, MRI findings, hypotonia, behavioral issues, distinctive hand characteristics (such as brachydactyly, 5th finger clinodactyly, and polydactyly), and various ocular abnormalities like coloboma, hyperopia, and strabismus.
Case Presentation
Our patient presented to our clinic after targeted testing identified a familial variant in CSDE1. His past medical history includes autism spectrum disorder (ASD), speech delay, postural orthostatic tachycardia syndrome (POTS), attention-deficit/hyperactivity disorder (ADHD), anxiety, and sleep apnea. Several members of our patient’s family also have this genetic variant including his brother, sister, father, paternal aunt, and paternal uncle.
Diagnostic Workup
Our patient received targeted molecular testing of the CSDE1 gene after a variant (c.1087C>T) had been identified in his brother. Cascade screening revealed the variant in multiple paternal family members, including the proband's father, sister, paternal uncle, and paternal aunt.
Treatment and Management
We are continuing to follow our patient and have ordered additional molecular testing with exome sequencing to identify possible etiologies for his other medical problems, including POTS. Testing is currently pending for other relatives who are interested in genetic workup.
Outcome and Follow-Up
Several of the proband's family members have since pursued targeted testing of the CSDE1 gene. Results are pending.
Discussion
The CSDE1 c.1087C>T (p.R363*) variant is a nonsense mutation believed to cause either protein truncation or nonsense-mediated decay, a recognized disease mechanism linked to CSDE1-associated neurodevelopmental disorder. To date, fewer than 50 individuals with pathogenic or likely pathogenic variants in CSDE1 have been described in literature. To our knowledge, this is the largest familial cohort with a novel variant to date. As a result, this highlights potential expansion of phenotype as well as highlights the variable expressivity of this disease. It is likely that a more complete picture of the phenotype will be developed with time and additional research.
Conclusion
Our patient’s presentation matches the phenotype of CSDE1-Associated Neurodevelopmental Disorder in that he has ASD, anxiety, ADHD, sleep issues, and experienced speech delay. We believe this genetic variant is significantly contributing to his features, as well as features of several of his family members. The patient’s case highlights the benefits of cascade screening with targeted testing. Additionally, it provides strong support for pathogenic classification of CSDE1 c.1087C>T (p.R363*).
The CSDE1 gene, also known as UNR, encodes an RNA-binding protein with a cold-shock domain that plays a role in translational reprogramming and is integral to many cellular processes, including cell cycle regulation, apoptosis, neuronal migration and differentiation, and dosage compensation. Most reported variants in CSDE1 are thought to result in loss of function; although many of these variants are de novo, inheritance from a mildly affected parent has also been documented.
Pathogenic or likely pathogenic variants in CSDE1 show incomplete penetrance and variable expressivity. Heterozygous variants in CSDE1 are associated with an autism spectrum and neurodevelopmental disorder phenotype, presenting with a range of neurodevelopmental symptoms from mild to severe intellectual disability, as well as delays in speech and motor development. Additional features observed in some affected individuals include sleep disturbances, seizures, macrocephaly, MRI findings, hypotonia, behavioral issues, distinctive hand characteristics (such as brachydactyly, 5th finger clinodactyly, and polydactyly), and various ocular abnormalities like coloboma, hyperopia, and strabismus.
Case Presentation
Our patient presented to our clinic after targeted testing identified a familial variant in CSDE1. His past medical history includes autism spectrum disorder (ASD), speech delay, postural orthostatic tachycardia syndrome (POTS), attention-deficit/hyperactivity disorder (ADHD), anxiety, and sleep apnea. Several members of our patient’s family also have this genetic variant including his brother, sister, father, paternal aunt, and paternal uncle.
Diagnostic Workup
Our patient received targeted molecular testing of the CSDE1 gene after a variant (c.1087C>T) had been identified in his brother. Cascade screening revealed the variant in multiple paternal family members, including the proband's father, sister, paternal uncle, and paternal aunt.
Treatment and Management
We are continuing to follow our patient and have ordered additional molecular testing with exome sequencing to identify possible etiologies for his other medical problems, including POTS. Testing is currently pending for other relatives who are interested in genetic workup.
Outcome and Follow-Up
Several of the proband's family members have since pursued targeted testing of the CSDE1 gene. Results are pending.
Discussion
The CSDE1 c.1087C>T (p.R363*) variant is a nonsense mutation believed to cause either protein truncation or nonsense-mediated decay, a recognized disease mechanism linked to CSDE1-associated neurodevelopmental disorder. To date, fewer than 50 individuals with pathogenic or likely pathogenic variants in CSDE1 have been described in literature. To our knowledge, this is the largest familial cohort with a novel variant to date. As a result, this highlights potential expansion of phenotype as well as highlights the variable expressivity of this disease. It is likely that a more complete picture of the phenotype will be developed with time and additional research.
Conclusion
Our patient’s presentation matches the phenotype of CSDE1-Associated Neurodevelopmental Disorder in that he has ASD, anxiety, ADHD, sleep issues, and experienced speech delay. We believe this genetic variant is significantly contributing to his features, as well as features of several of his family members. The patient’s case highlights the benefits of cascade screening with targeted testing. Additionally, it provides strong support for pathogenic classification of CSDE1 c.1087C>T (p.R363*).