Prenatal phenotype of Kabuki syndrome: A case series and literature review

Abstract

Objectives Kabuki syndrome (KS) is a genetic disorder characterized by intellectual disability, facial dysmorphism and congenital anomalies. We aim to investigate the prenatal features of fetuses with KS and to provide a comprehensive review of the literature on prenatal sonographic abnormalities associated with KS. Methods We retrospectively reviewed the prenatal ultrasound findings of all mothers of children with molecularly confirmed KS in Hong Kong, between 1991 and 2019. We also performed systematic review of the literature to identify studies on the prenatal findings in KS. Results We identified 11 cases with KS with detectable fetal ultrasound findings ranging from no detectable abnormalities to a variety of non‐specific findings including increased nuchal translucency, pleural effusion, cardiac anomalies, renal anomalies, intrauterine growth restriction, polyhydramnios, oligohydramnios and single umbilical artery. In combining our cases with the 77 cases published, 42 (50.6%) of them had more than one abnormal antenatal ultrasound finding. The most frequent ultrasound features observed were cardiac anomalies (49.4%), followed by polyhydramnios (28.9%), genitourinary anomalies (26.5%), single umbilical artery (15.7%), intrauterine growth restriction (14.5%) and hydrops fetalis/pleural effusion/ascites (12.0%). Conclusions These cases demonstrate the prenatal phenotypic heterogeneity associated with KS. Although the ultrasound abnormalities are non‐specific, KS should be considered in the differential diagnosis when these fetal findings following normal microarray analysis/karyotyping.

Molecular Approaches in Fetal Malformations, Dynamic Anomalies and Soft Markers: Diagnostic Rates and Challenges—Systematic Review of the Literature and Meta-Analysis

“…For the quantitative analysis, 40 articles [121, were secondarily excluded. Of these, three papers focused on fetal demises or stillbirths [256][257][258], three papers focused on information postmortem [242,250,254], three were case reports [238,246,252], five focused on a single specific phenotype [240,241,248,261,274], three presented inhomogeneity in inclusion criteria and chromosomal anomalies/CNV assessment [239,251,262], six included both fetuses and postnatal cases [244,249,253,259,260,269], three focused on candidate genes [243,247,263], three focused on recurrent phenotypes or previously described cohorts [245,255,272], five were excluded for the lack of inclusion or eligibility criteria [264,265,268,271,276], two were excluded for the higher a priori risk for consanguinity and recurrence [266,270], one because parents were tested for recessive disorders [267], two because they focused on gene panels [273,275], and one due to the postnatal diagnosis [121].…”

Underlying genetic etiologies of congenital diaphragmatic hernia

“…20,36,37 Variants in KMT2D cause Kabuki syndrome 1 whose prenatal presentation may include an abnormal maternal serum screening, polyhydramnios, fetal growth restriction, single umbilical artery, orofacial clefting, and cardiovascular, gastrointestinal, renal, and/or genitourinary anomalies. 38,39 Variants in MYRF are associated with cardiac-urogenital syndrome which is characterized by a wide variety of cardiac anomalies, pulmonary hypoplasia, which can be independent of CDH, and genitourinary anomalies. 36,40 Pathogenic ZFPM2 variants can cause both isolated CDH and CDH associated with cardiovascular anomalies.…”

Emerging technologies for prenatal diagnosis: The application of whole genome and RNA sequencing

“…In addition, prenatal sequencing has also been extremely helpful in elucidating and expanding foetal phenotypes of known disease-causing genes. [10][11][12] Exome testing, however, only covers a fraction of the entire genome, and is not adequate for the detection of variants in promoters and other regulatory elements, intronic, and intergenic regions, and of small copy number variants that would go undetected by chromosome or CMA analysis. Hence, with technologies rapidly improving and decreasing sequencing costs, the use of prenatal whole genome sequencing (WGS) is being investigated, as discussed below.…”

“…Studies on postnatal testing report that sequencing can lead to up to 40% incremental diagnostic yield in addition to the 25%–40% by standard karyotyping and chromosomal microarray (CMA) analysis. In addition, prenatal sequencing has also been extremely helpful in elucidating and expanding foetal phenotypes of known disease‐causing genes 10–12 …”