Germline mosaicism in a family with MBD5 haploinsufficiency

Abstract

Haploinsufficiency of the methyl-CpG-binding domain protein 5 (MBD5) gene causes a neurodevelopmental disorder that includes intellectual disability, developmental delay, speech impairment, seizures, sleep disturbances, and behavioral difficulties. Microdeletion of 2q23.1 is the most common cause of haploinsufficiency, although MBD5 haploinsufficiency may also cause this genetic disorder. We report a family harboring a heterozygous loss-of-function variant in MBD5 (NM_018328.5:c.728delC; p.Pro243Hisfs*26), which includes three affected siblings with varying phenotypic features. Both parents were phenotypically normal but deep coverage sequencing of the parents showed germline mosaicism in the mother.

Keywords: generalized tonic seizures; intellectual disability, mild; intellectual disability, moderate.

Figure 1.

Pedigree showing individuals who are heterozygous for the variant NM_018328.5:c.728delC. Affected individuals are marked as black filled symbols and the mosaic individual is indicated with a gray filled symbol.

Figure 2.

Individual II-1: widow's peak, narrow bitemporal diameter, thick eyebrows, small mouth, and short palpebral fissures.

Figure 3.

Individual II-1: brachycephaly, low anterior hairline, high nasal bridge, mild micrognathia, and large low-set ears with mild posterior rotation.

Figure 4.

Individual II-1: sandal gap between first and second toes.

Figure 5.

Individual II-5: Low anterior hairline, widow's peak, thick arched eyebrows, short palpebral fissures, bulbous nasal tip, small mouth, and low-set ears.