Four-Generation Pedigree of Monozygotic Female Twins Reveals Genetic Factors in Twinning Process by Whole-Genome Sequencing

Abstract

Familial monozygotic (MZ) twinning reports are rare around the world, and we report a four-generation pedigree with seven recorded pairs of female MZ twins. Whole-genome sequencing of seven family members was performed to explore the featured genetic factors in MZ twins. For variations specific to MZ twins, five novel variants were observed in the X chromosome. These candidates were used to explain the seemingly X-linked dominant inheritance pattern, and only one variant was exonic, located at the 5'UTR region of ZCCHC12 (chrX: 117958597, G > A). Besides, consistent mitochondrial DNA composition in the maternal linage precluded roles of mitochondria for this trait. In this pedigree, autosomes also contain diverse variations specific to MZ twins. Pathway analysis revealed a significant enrichment of genes carrying novel SNVs in the epithelial adherens junction-signaling pathway (p = .011), contributed by FGFR1, TUBB6, and MYH7B. Meanwhile, TBC1D22A, TRIOBP, and TUBB6, also carrying similar SNVs, were involved in the GTPase family-mediated signal pathway. Furthermore, gene-set enrichment analysis for 533 genes covered by copy number variations specific to MZ twins illustrated that the tight junction-signaling pathway was significantly enriched (p < .001). Therefore, the novel changes in the X chromosome and the provided candidate variants across autosomes may be responsible for MZ twinning, giving clues to increase our understanding about the underlying mechanism.

The mystery of monozygotic twinning II: What can monozygotic twinning tell us about Amyoplasia from a review of the various mechanisms and types of monozygotic twinning?

“…Many attempts to identify the gene or genes and mechanism or mechanisms for their familial form of MZ twinning have been undertaken, but the mechanism(s) have not been determined (Shur, 2009). One X‐linked dominant family has also been reported (Liu et al, 2018).…”

“…Harvey et al (1977); Parisi et al (1983) suggested there might be rare families in which a form of familial MZ twinning occurs. Recently, clusters of familial MZ twinning have been identified in India and Brazil (Cyranoski, 2009; Liu et al, 2018; Machin, 2009a, 2009b; Matte et al, 1996). These familial MZ twins appear NOT to have an increase in congenital anomalies, nor has TTTS been reported in spite of single placentas.…”

Two is a Crowd

“…But indeed, monozygotic twinning occurs at a relatively constant rate of three to five in 1,000 births worldwide, supporting the view that it represents a random and/or genetic event (Tarlatzis et al, ). A paper by Liu et al () described a four‐generation pedigree of monozygotic female twins revealing novel genetic variants specific to monozygotic twins in the X chromosome.…”

Naturally monozygotic quadruplets in a Braford cow confirmed by DNA analysis: A case report

“…On the other hand, Echternkamp, Thallman, Cushman, Allan, and Gregory (2007) and Morris et al (2010) selected lineages for multiple ovulation, with the consequent increment in conception rate (DZ twins or multiple births). While the inheritance of MZ twins in cattle has not been reported and has been discussed for decades in many species, some works in human beings suggest a genetic background (Liu et al., 2018; Machin, 2009). If those same mechanisms are presented in cattle, the female in the current study and her daughters could be the founders of a lineage to study a possible genetic or epigenetic mechanism behind MZ multiple births in cattle.…”