A 3-year-old boy presents with moderate intellectual disability, distinctive facial features (brachycephaly, broad square face, deep-set eyes, tented upper lip), and a striking behavioral phenotype including severe sleep disturbance with daytime somnolence and nighttime awakening. His parents are unaffected and non-consanguineous. Chromosomal microarray reveals a heterozygous interstitial microdeletion at 17p11.2 encompassing the RAI1 gene, as marked **A** in the inheritance diagram. Which of the following best describes the inheritance pattern and recurrence risk in this family?

Why "Autosomal dominant de novo mutation with recurrence risk <1% from parental germline; >95% of cases are sporadic" is right

Smith-Magenis Syndrome (SMS) is caused by a heterozygous 17p11.2 microdeletion or RAI1 point mutation, showing autosomal dominant inheritance. However, the defining feature is that >95% of cases arise de novo in unaffected, non-consanguineous parents, making this a sporadic presentation. The recurrence risk is <1% (accounting for rare gonadal mosaicism), which is why parental chromosomal microarray is normal in this case. This de novo dominant pattern is pathognomonic for SMS and distinguishes it from autosomal recessive conditions. The clinical phenotype—intellectual disability, distinctive facies, inverted melatonin rhythm causing sleep disturbance, and self-injurious behaviors—is driven by haploinsufficiency of the RAI1 transcription regulator (Smith ACM, GeneReviews; Slager RE et al., Nat Genet 2003).

Why each distractor is wrong

Smith ACM, GeneReviews — Smith-Magenis Syndrome; Slager RE et al., Nat Genet 2003