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A recurrent de novo missense pathogenic variant in SMARCB1 causes severe intellectual disability and choroid plexus hyperplasia with resultant hydrocephalus

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Key Genetic Findings:

  • The Mutation: All four individuals evaluated in this study shared the exact same de novo missense mutation: c.110G>A (p.Arg37His) located in exon 2 (the DNA-binding domain) of the SMARCB1 gene.

  • “De Novo” Nature: “De novo” means the mutation occurred spontaneously in the child and was not inherited from either parent.

  • Distinct Mechanism: SMARCB1 mutations are typically associated with conditions like Rhabdoid Tumor Predisposition Syndrome (RTPS1), Schwannomatosis, or Coffin-Siris Syndrome (CSS). However, this specific p.Arg37His variant causes a unique condition separate from typical Coffin-Siris syndrome, likely functioning through a gain-of-function or dominant-negative mechanism.

Clinical Features & Shared Symptoms

The study tracked four girls carrying this variant and identified several shared clinical characteristics:

  1. Hydrocephalus & Choroid Plexus Hyperplasia (100% of cases): * Excess cerebrospinal fluid (CSF) production caused enlargement of brain ventricles (hydrocephalus).

    • This excess fluid was caused by growth/overdevelopment of the choroid plexus (choroid plexus hyperplasia).

  2. Severe Intellectual & Motor Disability (100% of cases): * Marked motor delays, severe speech delay/nonverbal communication, and generalized muscle weakness (hypotonia).

  3. Severe Neonatal Feeding Difficulties (100% of cases): * Early feeding issues requiring specialized nutritional support (e.g., tube feedings).

  4. Sleep Apnea (100% of cases): * Obstructive and/or central sleep apnea during nighttime, attributed partly to structural brainstem/pons characteristics.

  5. Vision & Eye Issues (High Frequency): * Severe myopia (nearsightedness), cortical visual impairment (CVI), strabismus, or nystagmus.

  6. Other Findings: * Transient or intermittent anemia , minor kidney or cardiac structural anomalies , and joint hypermobility.

Key Takeaways & Recommendations for Families

If a family member has been diagnosed with a p.Arg37His variant in SMARCB1, the study suggests several proactive clinical management and monitoring steps to discuss with a medical team:

  • Neurological & Neurosurgical Monitoring:

    • Regular neurological evaluation and brain imaging (MRI) are crucial to monitor for signs of increased intracranial pressure (headaches, vomiting, lethargy) and hydrocephalus.

    • Surgical interventions (such as shunt placement or revision) may be needed to manage brain fluid pressure.

  • Sleep Evaluation:

    • Because sleep apnea (central or obstructive) is prevalent, performing a polysomnogram (sleep study) is strongly recommended to determine if night support (e.g., BiPAP or oxygen) is required.

  • Gastrointestinal & Nutritional Support:

    • Early evaluation by a pediatric gastroenterologist or feeding team is essential to ensure safe nutrition, manage GI dysmotility, and evaluate the need for enteral feeding tube support.

  • Ophthalmology & Hearing Checks:

    • Routine visual evaluations should be established early to manage high myopia, strabismus, or other eye complications. Hearing evaluations are also advised.

  • Kidney & Heart Screenings:

    • Baseline screening via abdominal ultrasound (to check for kidney issues like reflux or hydronephrosis) and echocardiogram (cardiac ultrasound) are valuable management steps.

  • Routine Blood Monitoring:

    • Simple periodic Complete Blood Counts (CBC) are recommended to check for transient anemia or low platelet counts (thrombocytopenia).

  • Family Genetic Counseling:

    • Because these reported cases occurred de novo (spontaneous), the recurrence risk for future pregnancies in the parents is generally very low, though genetic counseling is recommended for personalized risk assessment and guidance.