Disruption of MBD5 contributes to a spectrum of psychopathology and neurodevelopmental abnormalities

Abstract

Microdeletions of chromosomal region 2q23.1 that disrupt MBD5 (methyl-CpG-binding domain protein 5) contribute to a spectrum of neurodevelopmental phenotypes; however, the impact of this locus on human psychopathology has not been fully explored. To characterize the structural variation landscape of MBD5 disruptions and the associated human psychopathology, 22 individuals with genomic disruption of MBD5 (translocation, point mutation and deletion) were identified through whole-genome sequencing or cytogenomic microarray at 11 molecular diagnostic centers. The genomic impact ranged from a single base pair to 5.4 Mb. Parents were available for 11 cases, all of which confirmed that the rearrangement arose de novo. Phenotypes were largely indistinguishable between patients with full-segment 2q23.1 deletions and those with intragenic MBD5 rearrangements, including alterations confined entirely to the 5'-untranslated region, confirming the critical impact of non-coding sequence at this locus. We identified heterogeneous, multisystem pathogenic effects of MBD5 disruption and characterized the associated spectrum of psychopathology, including the novel finding of anxiety and bipolar disorder in multiple patients. Importantly, one of the unique features of the oldest known patient was behavioral regression. Analyses also revealed phenotypes that distinguish MBD5 disruptions from seven well-established syndromes with significant diagnostic overlap. This study demonstrates that haploinsufficiency of MBD5 causes diverse phenotypes, yields insight into the spectrum of resulting neurodevelopmental and behavioral psychopathology and provides clinical context for interpretation of MBD5 structural variations. Empirical evidence also indicates that disruption of non-coding MBD5 regulatory regions is sufficient for clinical manifestation, highlighting the limitations of exon-focused assessments. These results suggest an ongoing perturbation of neurological function throughout the lifespan, including risks for neurobehavioral regression.

Figure 1

Structural alterations disrupting MBD5. (a) UCSC genome browser (genome build hg18) demonstrating 22 cases of intragenic MBD5 and larger 2q23.1 disruptions (red bars) identified by cytogenomic microarray. MBD5 is at position 148,495,050–148,987,514 and contains 15 exons of which exons 1–5 are the non-coding 5′UTR and exons 6–15 are protein coding. Cases 5, 6, 16, 20 and 21 involve disruptions confined to the non-coding region of MBD5 and Case 22 is confined to the coding region of MBD5, while all other cases overlap at least one other gene. Asterisks (*) denote a single base pair change resulting in a frameshift mutation in Case 20, a two base pair deletion in Case 21, and the translocation breakpoint in Case 22. (b) Whole genome sequencing of Case 22 delineated that an apparently balanced translocation between chromosomes 2 and 5 directly disrupted MBD5 at 2q23.1 and did not affect any annotated functional sequence on chromosome 5. A local microinversion of 169 bases was also detected at the breakpoint of the chromosome 5 material on the der(2) chromosome. The GTG-banded idiograms depict the normal chromosomes 2 and 5 as well as the derivative chromosomes from the translocation. The breakpoint regions on the derivative chromosomes are expanded in the middle, providing genomic coordinates, cytogenetic bands, precise breakpoints (dotted red line), and surrounding nucleotide sequence of the junctions including microhomology (highlighted in yellow) at the translocation and inversion breakpoints. The 5′ and 3′ non-coding UTR regions of the disrupted MBD5 transcript are highlighted in green, the translated region is highlighted in blue, and exons are denoted by rectangles.

Figure 2

Clinical features associated with MBD5 disruption. Patients with MBD5 deletions have a broad range of physical features both in type and severity. A, Case 4 (6 year 9 month old female) has a round face, midface hypoplasia, flat nose and thin upper lip, which along with ID/DD, hearing loss, and unusual behavior of self-injury and altered sleep cycle, were highly suggestive of SMS. Cytogenomic microarray demonstrated a de novo deletion (153 kb) of the MBD5 5′ UTR while subsequent sequencing of the RAI1 gene associated with SMS was negative. B, Case 15 (7 year 9 month old male) has brachycephaly, midface hypoplasia, depressed nasal bridge, a thin and tented upper lip, open mouth and dental crowding. C, Case 12 (3 year old female) has dysmorphic facies with synophrys, slightly downslanting palpebral fissures, tented upper lip, depressed nasal bridge with an upturned nose and somewhat prominent ears with attached lobes as well as a low posterior hairline, right supernumerary nipple, short neck, short thumbs and fifth fingers, and mildly dysplastic fifth toenails. D, Case 8 (2 year old male) has an open mouth with downturned corners, a depressed nasal bridge, and an overfolded helix. E, Case 11 (20 year old female) has a thin upper lip, a slightly smooth philtrum, mild epicanthal folds with slightly upslanting palpebral fissures and a prominent columella with a thickened nasal tip. F, Case 8 (14 year old male) has mildly prominent and overfolded ears with thickened helices. G, Case 9 (12 year old male) is the brother of Case 8 and has similar atypical ears. H, Case 16 (7 year old male) has a thin upper lip, long philtrum, prominent nasal bridge, arched eyebrows, epicanthal folds and almond-shaped eyes.