Novel variants in <i>STAG2</i> and <i>PKD1</i> associate with multiple congenital malformations and autosomal dominant polycystic kidney disease in a Chinese family: A case report and literature review

Cohesinopathies are rare multisystem disorders caused by defects in the cohesin complex, which is critical for chromosome segregation, DNA repair, replication, heterochromatin formation and gene transcription regulation. Stromal antigen 2 (STAG2), a key cohesin component, is linked to neurodevelopmental disorders such as X-linked holoprosencephaly 13 and Mullegama-Klein-Martinez syndrome (MKMS). Polycystic kidney disease (PKD), particularly autosomal dominant PKD (ADPKD), is characterized by renal cysts and is commonly associated with variants in the <i>PKD1</i> gene. In the present study, a Chinese family was enrolled, which included an infant diagnosed with MKMS and familial PKD. Trio whole-exome sequencing (trio-WES) was performed to identify a heterozygous in-frame deletion variant in <i>STAG2</i> [NM_001042750.2:c.1775_1777del, p.(Pro592del)] and a heterozygous frameshift variant in <i>PKD1</i> [NM_001009944.3:c.8985delC, p.(Ser2996fs*78)] in the proband. The <i>STAG2</i> variant [c.1775_1777del, p.(Pro592del)] was confirmed by Sanger sequencing to be absent in other family members and was therefore <i>de novo</i>. By contrast, the <i>PKD1</i> variant [c.8985delC, p.(Ser2996fs*78)] was identified in the mother, aunt and grandmother of the proband. The proband exhibited clinical features consistent with <i>STAG2</i>-related disorders, including seizures, global developmental delay, short stature, microcephaly, hypotonia, dysmorphic features, incomplete cleft palate, micrognathia, spina bifida occulta and duplication of the middle phalanx of the third finger on the left hand. Comparative analysis of the present patient and previously reported cases with <i>STAG2</i> variants suggested that intellectual disability, brain abnormalities, dysmorphic features and skeletal anomalies are the core clinical features of <i>STAG</i>2-related disorders. Furthermore, familial PKD was observed in the proband, mother, aunt and grandmother, confirming an autosomal dominant inheritance pattern associated with the <i>PKD1</i> variant. In summary, the present report identified a novel <i>de novo STAG2</i> variant associated with multisystem congenital malformations and a novel familial <i>PKD1</i> variant causing ADPKD, expanding the genetic and phenotypic spectrum of these disorders. The present findings highlight the utility of WES in diagnosing complex genetic conditions.