Members of the TGF-beta superfamily, which includes TGF-betas, growth differentiation factors, bone morphogenetic proteins, activins, inhibins, and glial cell line-derived neurotrophic factor, are synthesized as prepropeptide precursors and then processed and secreted as homodimers or heterodimers. Most ligands of the family signal through transmembrane serine/threonine kinase receptors and SMAD proteins to regulate cellular functions. Many studies have reported the characterization of knockout and knock-in transgenic mice as well as humans or other mammals with naturally occurring genetic mutations in superfamily members or their regulatory proteins. These investigations have revealed that TGF-beta superfamily ligands, receptors, SMADs, and upstream and downstream regulators function in diverse developmental and physiological pathways. This review attempts to collate and integrate the extensive body of in vivo mammalian studies produced over the last decade.

Despite their clinical significance, characterization of balanced chromosomal abnormalities (BCAs) has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and revealed complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. This study proposes that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements, and provides insight into novel pathogenic mechanisms such as altered regulation due to changes in chromosome topology.