22q11.2 duplication syndrome and LZTR1-related Noonan syndrome type 10 overlapping phenotypes in a dual diagnosis - fetal hydrops: a case report
TL;DR
Fetuses carrying both a pathogenic copy number variant of duplication in the 22q11.2 region and a heterozygous pathogenic missense variant of the LZTR1 gene simultaneously constitute the main genetic basis for its multisystem abnormalities and severe hydrops.
Abstract
Nonimmune factors are the most common cause of fetal hydrops, which are characterized by the accumulation of pathological fluid due to various causes. The etiology of this disease is complex, with a relatively high mortality rate, and the prognosis largely depends on the underlying cause. Notably, fetal hydrops attributable to genetic causes, such as chromosomal abnormalities or gene mutations, are typically associated with a poor prognosis. A fetus diagnosed with severe nonimmune fetal hydrops at 27 weeks of gestation presented with multiple abnormalities on prenatal ultrasound, including progressively thickened nuchal translucency (NT) and nuchal fold (NF), cystic hygroma, pleural effusion, and renal pelvis duplication. Amniotic fluid cytogenetic analysis revealed a normal karyotype. Integrated chromosomal microarray analysis (CMA) and trio-based whole-exome sequencing (Trio-WES) revealed a pathogenic 2.82 Mb duplication at chromosome 22q11.21, designated as arr[GRCh37] 22q11.21(18984188–21804597)x3, associated with 22q11.2 duplication syndrome, which was inherited from the father. Additionally, a heterozygous missense variant in the LZTR1 gene NM_006767.3: c.848G > A (p.Arg283Gln) was detected and classified as pathogenic, associated with Noonan syndrome type 10, maternally inherited. After comprehensive counseling and careful consideration, the parents elected to terminate the pregnancy. This study revealed that fetuses carrying both a pathogenic copy number variant of duplication in the 22q11.2 region and a heterozygous pathogenic missense variant of the LZTR1 gene (c.848G > A) simultaneously constitute the main genetic basis for its multisystem abnormalities and severe hydrops. This study highlights the role of multiple genetic superimposition effects in the formation of complex fetal phenotypes and emphasizes that in genetic counseling and prenatal diagnosis, a combined strategy of CMA and Trio-WES should be adopted to improve the detection rate of complex genetic diseases and the accuracy of recurrence risk assessment.