Germline mosaicism in a family with MBD5 haploinsufficiency

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Molecular Biology

Background:

• Haploinsufficiency of the methyl-CpG-binding domain protein 5 (MBD5) gene is linked to neurodevelopmental disorders.
• Microdeletion of 2q23.1 is a common cause, but MBD5 gene variants can also lead to this condition.

Purpose of the Study:

• To investigate the genetic basis of a neurodevelopmental disorder in a family with suspected MBD5 gene involvement.
• To identify the inheritance pattern and mechanism of MBD5-related disorder within the family.

Main Methods:

• Whole exome sequencing of affected siblings and parents.
• Deep coverage sequencing to investigate parental germline mosaicism.
• Analysis of a heterozygous loss-of-function variant in the MBD5 gene (NM_018328.5:c.728delC; p.Pro243Hisfs*26).

Main Results:

• Identified a heterozygous loss-of-function variant in MBD5 in three affected siblings.
• Phenotypic features varied among the affected siblings.
• Germline mosaicism in the mother was confirmed through deep coverage sequencing, despite her normal phenotype.

Conclusions:

• MBD5 haploinsufficiency due to a novel loss-of-function variant can cause a spectrum of neurodevelopmental disorders.
• Maternal germline mosaicism is a significant factor in the inheritance of MBD5-related disorders.
• Understanding MBD5 gene function is crucial for diagnosing and managing neurodevelopmental conditions.