Twin study confirms virtually identical prenatal alcohol exposures can lead to markedly different fetal alcohol spectrum disorder outcomes-fetal genetics influences fetal vulnerability

Abstract

Background: Risk of fetal alcohol spectrum disorder (FASD) is not based solely on the timing and level of prenatal alcohol exposure (PAE). The effects of teratogens can be modified by genetic differences in fetal susceptibility and resistance. This is best illustrated in twins.

Objective: To compare the prevalence and magnitude of pairwise discordance in FASD diagnoses across monozygotic twins, dizygotic twins, full-siblings, and half-siblings sharing a common birth mother.

Methods: Data from the Fetal Alcohol Syndrome Diagnostic & Prevention Network clinical database was used. Sibling pairs were matched on age and PAE, raised together, and diagnosed by the same University of Washington interdisciplinary team using the FASD 4-Digit Code. This design sought to assess and isolate the role of genetics on fetal vulnerability/resistance to the teratogenic effects of PAE by eliminating or minimizing pairwise discordance in PAE and other prenatal/postnatal risk factors.

Results: As genetic relatedness between siblings decreased from 100% to 50% to 50% to 25% across the four groups (9 monozygotic, 39 dizygotic, 27 full-sibling and 9 half-sibling pairs, respectively), the prevalence of pairwise discordance in FASD diagnoses increased from 0% to 44% to 59% to 78%. Despite virtually identical PAE, 4 pairs of dizygotic twins had FASD diagnoses at opposite ends of the fetal alcohol spectrum-Partial Fetal Alcohol Syndrome versus Neurobehavioral Disorder/Alcohol-Exposed.

Conclusion: Despite virtually identical PAE, fetuses can experience vastly different FASD outcomes. Thus, to protect all fetuses, especially the most genetically vulnerable, the only safe amount to drink is none at all.

Keywords: fetal alcohol spectrum disorder; genetics; prenatal alcohol exposure; twins.

Figure 1.. FASD 4-Digit Diagnostic Code.

A) Abbreviated case-definitions for the fetal alcohol spectrum disorder (FASD) 4-Digit Code [2]. The 4-Digit Code 3434 is one of 12 4-Digit Codes that fall under the diagnostic category FAS. B) The Rank 4 FAS facial phenotype requires 3 features: 1) palpebral fissure lengths 2 or more standard deviations below the mean; 2) a smooth philtrum (Rank 4 or 5 on the University of Washington Lip-Philtrum Guide); and 3) a thin upper lip (Rank 4 or 5 on the University of Washington Lip-Philtrum Guide). C and D) The 4-Digit Code produces four diagnostic subgroups under the umbrella of FASD: FAS (Diagnostic Categories A, B), PFAS (Diagnostic Category C), SE/AE (Diagnostic Categories E, F), and ND/AE (Diagnostic Categories G, H). Abbreviations: CNS: central nervous system; H: height percentile; W: weight percentile.

Figure 1.. FASD 4-Digit Diagnostic Code.

A) Abbreviated case-definitions for the fetal alcohol spectrum disorder (FASD) 4-Digit Code [2]. The 4-Digit Code 3434 is one of 12 4-Digit Codes that fall under the diagnostic category FAS. B) The Rank 4 FAS facial phenotype requires 3 features: 1) palpebral fissure lengths 2 or more standard deviations below the mean; 2) a smooth philtrum (Rank 4 or 5 on the University of Washington Lip-Philtrum Guide); and 3) a thin upper lip (Rank 4 or 5 on the University of Washington Lip-Philtrum Guide). C and D) The 4-Digit Code produces four diagnostic subgroups under the umbrella of FASD: FAS (Diagnostic Categories A, B), PFAS (Diagnostic Category C), SE/AE (Diagnostic Categories E, F), and ND/AE (Diagnostic Categories G, H). Abbreviations: CNS: central nervous system; H: height percentile; W: weight percentile.

Figure 2.. Twin/Sibling Pairwise Concordance in FASD outcomes and prenatal/postnatal risks.

Monozygotic twins, dizygotic twins, full siblings and half siblings share 100%, 50%, 50% and 25% of their genome respectively as depicted by the first set of bars. If fetal genetics is modifying the teratogenic impact of PAE, the pattern of pairwise concordance reflected in the bars for each FASD outcome will more closely resemble the pattern of bars for Genome Shared than the patterns of bars reflecting pairwise concordance in Alcohol Rank, other Prenatal Risks or Postnatal Risks. The bar patterns across all FASD outcomes are far more reflective of the pattern of bars for Genome Shared than the pattern of bars for Alcohol Rank, Prenatal Risk Rank or Postnatal Risk Rank. Although the bar pattern for Postnatal Risk Rank resembles the bar pattern for Face Rank, discordance in postnatal risk factors cannot be contributing to discordance in Face Rank because only prenatal factors can impact facial morphology. Since the FAS facial phenotype, as defined by the 4-Digit Code, is so specific to (caused only by) PAE, the most compelling evidence supporting the role genetics plays in modifying the teratogenic impact of PAE is illustrated in how highly correlated the bar patterns are between Genome Shared and Face Rank and how poorly correlated the bar patterns are between Face Rank and Alcohol Rank (especially between monozygotic and dizygotic twins with virtually identical PAE).