MBD5 Haploinsufficiency

Clinical characteristics: MBD5 haploinsufficiency is a neurodevelopmental disorder characterized by developmental delay, intellectual disability, severe speech impairment, seizures, sleep disturbances, and abnormal behaviors. Most children lack speech entirely or have single words, short phrases, or short sentences. Seizures are present in more than 80% of children; onset is usually around age two years. Sleep disturbances, present in about 90%, can result in excessive daytime drowsiness. Abnormal behaviors can include autistic-like behaviors (80%) and self-injury and aggression (>60%).

Diagnosis/testing: The diagnosis of MBD5 haploinsufficiency is established in a proband by identification on molecular genetic testing of a heterozygous deletion of 2q23.1 encompassing all or part of MBD5, or of an intragenic MBD5 pathogenic variant.

Management: Treatment of manifestations: A multidisciplinary approach that typically includes specialists in clinical genetics, neurology, child development, behavioral therapy, nutrition/feeding, speech and language therapy, and occupational and physical therapy is recommended. Infants benefit from enrollment in an early-intervention program, and school-age children benefit from an individualized educational program. Speech therapy (including nonverbal methods of communication) should be introduced early. Seizures, behavior problems, sleep disturbances, and constipation are treated in a routine manner. Feeding therapy with gastrostomy tube feeding as needed; treatment of hip dysplasia and scoliosis per orthopedist; treatment of cardiovascular anomalies per cardiologist; family support including social work involvement and care coordination.

Surveillance: Periodic neurodevelopmental and behavioral evaluations to assist in the management of cognitive issues, behavior issues, and sleep disturbance. Assess for seizures, feeding issues, constipation, and family support needs at each visit. Clinical assessment for scoliosis annually.

Genetic counseling: MBD5 haploinsufficiency is an autosomal dominant disorder typically caused by a de novo genetic alteration. To date, parent-to-child transmission of a 2q23.1 deletion that encompasses all or part of MBD5 has not been reported. Parent-to-child transmissions of MBD5 intragenic deletions and pathogenic sequence variants have been reported. Rarely, parent-to-child transmission of an unbalanced derivative chromosome involving the 2q23.1 region occurs. Once the genetic alteration resulting in MBD5 haploinsufficiency has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.