We first diagnosed SETD5 mutated fetuses prenatal, manifesting clinically with an ostium primum atrial septal defect, potential upper ventricular septal anomaly, and slight tricuspid regurgitation. An extensive exploration of both literature and public repositories was undertaken to accumulate insights on prior clinical instances related to SETD5 mutations (refer to Table 1). Congenital heart disease was present in 43.3% of the SEDT5 patients we enumerated, cystic hygroma was present in 3.3%, Intellectual disability/Developmental delay was present in 86.7%, Ritualized behavior and/or autism was present in 20%, Hypotonia/Epilepsy was present in 53.3%, Facial Dysmorphism was present in 96.7%, Postaxial polydactyly was present in 26.7%, Scoliosis, kyphosis or lordosis was present in 26.7%, Gastrointestinal abnormalities was present in 23.3% and Genitourinary defects was present in 10%。
Recent studies have underscored the pivotal influence of setd5 during embryonic maturation and growth phases. Notably, embryos devoid of setd5 manifest pronounced irregularities in areas such as neural tube organization, cardiac morphology, and the process of somitogenesis. A focused exploration into cardiovascular anomalies emphasized that close to half of the Setd5 null embryos manifested active cardiac pulsations by E9.5. This observation received validation through the comprehensive staining of cardinal cardiac differentiation indicators. In parallel, the absence of Setd5 in embryonic stem cells led to hindered cellular growth, augmented apoptotic activity, erratic cell cycle transitions, curtailed cardiomyocyte differentiation potential, and notable gene expression modulations [17]. A research endeavor led by Michelle Yu-Qing Cheung [18] employing a murine model unveiled the indispensability of setd5 in heart morphogenesis within the cardiopharyngeal mesoderm, with its haploinsufficiency culminating in outflow tract malformations in rodents. Synthesizing insights from our study with extant literature, there emerges a hypothesis positioning the SETD5 gene as a potential influencer in congenital heart disease etiology. Yet, the intricate pathways and modalities through which SETD5 steers cardiac morphogenesis and operationality are yet to be comprehensively delineated. As such, there is a pressing need for expanded research efforts focusing on the pathobiological intricacies linked with SETD5 variant manifestations.
In a pioneering documentation by Krzysztof Szczałuba [16], a unique familial instance of SETD5 mutation was brought to light, observed in a pair of siblings. The progenitor of this mutation was their father, manifesting only subtle cognitive challenges. Among the siblings, one exhibited a myriad of clinical features including a combined partial atrioventricular septal defect, patent ductus arteriosus, persistent left superior vena cava, alongside other morphological anomalies. The other sibling demonstrated a partial atrioventricular septal defect complemented by distinct developmental irregularities. In a separate study by Zöe Powis[19], an examination of 14 individuals with variations in the SETD5 gene was conducted. Predominantly, individuals in this grouping displayed overlapping phenotypes previously identified, encapsulating developmental lags and psychiatric challenges. Interestingly, within this group, two individuals were diagnosed with an accompanying partial atrioventricular septal defect, while another had a ventricular septal anomaly. Another notable contribution was from Lettie E. et al [20], highlighting an infantile case wherein SETD5 variations culminated in an echocardiographically-detected ventricular septal defect.
Based on the above findings and the clinical characteristics of the cases reported in this study, we confirm that congenital heart disease, including atrial and ventricular septal defects, is a prenatal clinical feature caused by mutations in this gene.
In addition to the prenatal case reported here, a case of prenatal cystic hygroma in early pregnancy associated with a mutation in SETD5 has been reported in the literature [21], which presented with cystic hygroma and a thickened nuchal fold during gestation, and the results of Microarray analysis of placental DNA were normal, however, facial deformities and early neurodevelopmental syndrome appeared in less than two years of age, and the analysis was performed by whole-exome sequencing, which revealed that there was a mutation in SETD5. Therefore, SETD5 mutations may manifest as atrial and ventricular septal defects and cystic hygroma in the prenatal period, and physicians should be alerted to the presence of these two phenotypes in the fetus during the prenatal period.
In this prenatal case, clinical manifestations such as atrial septal defect and the possibility of an upper ventricular septal defect were observed. Such conditions, which are prevalent within congenital heart diseases, are potentially manageable through surgical interventions postnatally, usually resulting in improved prognoses. Intriguingly, the implicated gene, SETD5, has been established as a significant contributor to neurodevelopmental anomalies, including intellectual disability (ID), autism spectrum disorders, and KBG syndromes. This gene also constitutes a vital component of the 3p25.3 microdeletion syndrome, particularly associated with three genes (THUMPD3, SETD5, and THUMPD3-AS1) [3, 22–24]. Detrimental alterations within SETD5 can profoundly influence patient survival and life quality. In the absence of comprehensive genetic testing for this case, cardiac ultrasonography might have been the sole criterion, fetal prognosis may be grossly misjudged based on cardiac ultrasound findings alone. With a plethora of clinical syndromes linked to congenital heart disease, the implementation of prenatal whole exome sequencing technology is pivotal. It lays the foundation for meticulous counseling, greatly enhancing the precision in prenatal diagnostic and prognostic assessments [25].
Table 1
Comparison of the Clinical Features Observed by previous study and in our case
Clinical feature | Our patient (n = 1) | Min Pan et al. (2020) (n = 1) | Szczaluba et al. al.(2016) (n = 3) | Grozeva et al. (2015) (n = 7) | Kuechler et al. (2015) (n = 2) | Powis et al. (2017) (n = 14) | Pascolini et al. (2022) (n = 1) | Rawlins et al. (2017) (n = 1) |
Age at last examination | fetus | 16 months | varied | varied | varied | varied | 8 years | 4 weeks |
Congenital heart defects | + | - | 2 | 2 | 0 | 8 | + | + |
cystic hygroma | - | + | 0 | 0 | 0 | 0 | - | - |
Intellectual disability /Developmental delay | NA | + | 3 | 7 | 2 | 11 | + | + |
Ritualized behavior and/or autism | NA | NA | 0 | 5 | 0 | NA | - | + |
Hypotonia/Epilepsy | NA | NA | 2 | NA | 0 | 14 | - | - |
Facial Dysmorphism | NA | + | 3 | 7 | 2 | 14 | + | + |
Postaxial polydactyly | NA | NA | 2 | 1 | 0 | 4 | + | - |
Scoliosis, kyphosis or lordosis | NA | NA | 0 | 4 | 0 | 4 | - | - |
Gastrointestinal abnormalities | NA | NA | 0 | 5 | 0 | 2 | - | - |
Genitourinary defects | NA | NA | 2 | 0 | 0 | 1 | - | - |
+, positive; -, negative; NA, not available