Further heterogeneity in Silver-Russell syndrome: PLAG1 deletion in association with a complex chromosomal rearrangement.

Silver-Russell syndrome (SRS) is a rare genetic condition primarily characterized by growth restriction and facial dysmorphisms. While hypomethylation of H19/IGF2:IG-DMR (imprinting control region 1 [IC1]) located at 11p15.5 and maternal uniparental disomy of chromosome 7 (upd[7]mat) are the most common genetic mechanisms responsible for SRS, the expanding body of literature describing alternative causative variants suggests SRS is a highly heterogeneous condition, also involving variation in the HMGA2-PLAG1-IGF2 pathway. We report a familial PLAG1 deletion in association with a complex chromosomal rearrangement. We describe two siblings with differing unbalanced chromosomal rearrangements inherited from a mother with a 5-breakpoint balanced complex rearrangement involving chromosomes 2, 8, and 21. The overlapping but diverse phenotypes in the siblings were characterized by shared SRS-like features, underlined by a PLAG1 whole gene deletion. Genetic analysis and interpretation was further complicated by a meiotic recombination event occurring in one of the siblings. This family adds to the limited literature available on PLAG1-related SRS. We have reviewed all currently known cases aiming to define the associated phenotype and guide future genetic testing strategies. The heterogeneity of SRS is further expanded by the involvement of complex cytogenomic abnormalities, imposing requirements for a comprehensive approach to testing and genetic counseling.

Atypical nested 22q11.2 duplications between LCR22B and LCR22D are associated with neurodevelopmental phenotypes including autism spectrum disorder with incomplete penetrance.

BACKGROUND: Chromosome 22q11.2 is susceptible to genomic rearrangements and the most frequently reported involve deletions and duplications between low copy repeats LCR22A to LCR22D. Atypical nested deletions and duplications are rarer and can provide a valuable opportunity to investigate the dosage effects of a smaller subset of genes within the 22q11.2 genomic disorder region. METHODS: We describe thirteen individuals from six families, each with atypical nested duplications within the central 22q11.2 region between LCR22B and LCR22D. We then compared the molecular and clinical data for patients from this study and the few reported atypical duplication cases, to the cases with larger typical duplications between LCR22A and LCR22D. Further, we analyzed genes with the nested region to identify candidates highly enriched in human brain tissues. RESULTS: We observed that atypical nested duplications are heterogeneous in size, often familial, and associated with incomplete penetrance and highly variable clinical expressivity. We found that the nested atypical duplications are a possible risk factor for neurodevelopmental phenotypes, particularly for autism spectrum disorder (ASD), speech and language delay, and behavioral abnormalities. In addition, we analyzed genes within the nested region between LCR22B and LCR22D to identify nine genes (ZNF74, KLHL22, MED15, PI4KA, SERPIND1, CRKL, AIFM3, SLC7A4, and BCRP2) with enriched expression in the nervous system, each with unique spatiotemporal patterns in fetal and adult brain tissues. Interestingly, PI4KA is prominently expressed in the brain, and this gene is included either partially or completely in all of our subjects. CONCLUSION: Our findings confirm variable expressivity and incomplete penetrance for atypical nested 22q11.2 duplications and identify genes such as PI4KA to be directly relevant to brain development and disorder. We conclude that further work is needed to elucidate the basis of variable neurodevelopmental phenotypes and to exclude the presence of a second disorder. Our findings contribute to the genotype-phenotype data for atypical nested 22q11.2 duplications, with implications for genetic counseling.