Previous studies have shown that fetal nasal bone anomaly can be used as an ultrasound soft marker for screening of fetal chromosomal aberrations, particularly trisomy 21 syndrome. Nasal bone abnormality is closely associated with Down syndrome in fetuses with special facial features such as low and flat nasal root, widened eye distance, and glassy eyes [2, 10–13]. In this study, chromosome abnormalities were found in 25 (24.5%) of 102 fetuses with abnormal nasal bone development, among which the majority (n = 15) had trisomy 21. The ratio was similar to some reports at home and abroad [5, 10, 14].
Fetal nasal bone anomaly has been reported to be associated with other rare diseases or syndromes with facial deformities such as Cri du chat (5p-) syndrome, Wolf-Hirschhorn (4p-) syndrome, and Fryns syndrome [1, 15, 16]. In our study, copy number variation was detected in 9 cases (8.8%), 4 of which were clearly pathogenic, resulting in diseases that also overlapped with the above reports. The first case was a 2.0 Mb deletion in chromosome 15q13.2q13.3. This missing region contains 7 OMIM genes and can cause 15q13.3 micro-deletion syndrome which is manifested as developmental retardation, mild to moderate learning disabilities, epilepsy, finger and toe deformities, and minor facial abnormalities. Another case had a 14.2 Mb deletion in the p15.31p14.3 region combined with a 3.1 Mb deletion in the q14.3 region of chromosome 15. The former partially overlaps with Cri du chat (5p-) syndrome and contains 20 OMIM genes including CTNND2 which is associated with mental retardation in Cri du chat syndrome. The latter contains 5 OMIM genes, including RASA1 and MEF2C, which are related to mental retardation, epilepsy, hypotonia, vascular malformation and more. One fetus with a 37 Mb deletion in chromosome 4p16.3p14 includes 115 OMIM genes and covers a key pathogenic region for Wolf-Hirschhorn syndrome. The last case had a 2.6 Mb deletion in the 15q24.1q24.2 region and includes 30 OMIM genes associated with 15q24 micro-deletion syndrome.
In addition to the four clearly pathogenic cases mentioned above, we found an additional case with a likely pathogenic mutation. This case carried a 994 Kb deletion in 16p12.2 which is a susceptibility site of neurocognitive disorder. The region contained 3 OMIM genes, including UQCRC2, EEF2K, and CDR2, which are found in less than 1% of the general population. Though the penetrance of the mutation was reportedly 12%, incomplete penetrance and variable expressivity make it difficult to predict the postnatal outcome , and family validation was refused. But the pathogenicity will remain unclear even if family verification is performed. This CNV was also found to be inherited in many cases from a phenotypically normal or only a mildly affected parent complicating phenotypic association and causality.
Four cases with uncertain clinical significance were detected in total. Of these cases, 2 (908 Kb duplication in 3p25.3p25.2 and 1.4 Mb duplication in 16p13.13p13.12), did not include parental verification and pathogenicity could not be determined. The other 2 cases carrying an 869 Kb deletion in 15q26.1 and a 422 Kb duplication in 15q13.3, respectively, were verified to be from parents with normal phenotypes. The q26.1 region of chromosome 15 contains 23 OMIM genes, and the fetuses carrying this CNV only showed signs of ventricular septal defects during ultrasonography not including nasal bone hypoplasia. The fetus with the duplication in 15q13.3, which harbors 2 OMIM genes (OTUD7A and CHRNA7), only displayed nasal bone abnormality during ultrasonography. This CNV partially overlapped with the recurrent region 15q13.3 when referring to the ClinGen database and the relapsed region had a triple dose effect score of 1 with an estimated penetrance of 5–10%. Fetuses with this variation develop phenotypes such as speech disorders, cognitive impairment, epilepsy, schizophrenia, and autism [18–22] although the pathogenicity of both of the above mutations remains unclear because they were found in the general population as well as in reportedly healthy parents . We can only infer that it is potentially benign based on the results of family verification and ultrasonography. Family verification is known to be important for variants of unknown significance (VUS). Previously, It was reported that VUS accounted for about 1.6–4.2% of total CNV [7, 24, 25] and was reduced to less than 1% by parental diagnoses although the clinical significance of 0.5-1% remains unclear .
In this retrospective study, 52 cases of solitary nasal bone anomaly were detected, of which 7 (13.5%) were chromosome aberrations. There were 50 cases of nonsolitary nasal bone anomaly, 18 (36.0%) of which had chromosomal abnormalities. The detection rate of nonsolitary nasal bone anomaly was significantly different from solitary nasal bone anomaly (χ2 = 7.0,P < 0.05), consistent with the results of Ting et al . We considered that the risk of chromosomal abnormalities was not limited to solitary nasal bone anomaly but was significantly increased when combined with other structural malformations. The detection of chromosomal abnormalities may also be related to ultrasonographic anomalies or a combination of prenatal diagnosis indications. Therefore, we believe that prenatal diagnosis is feasible for fetuses with nonsolitary nasal bone anomaly, and solitary nasal bone absence or hypoplasia cannot be ignored. The high prevalence of chromosomal abnormalities (13.5%) demonstrates that doctors experienced in genetic counseling should inform patients of the relationship between nasal bone anomaly and chromosomal aberrations. We recommend that doctors pay close attention to other indications for prenatal diagnosis, such as high risk for serology screening or age, then continue to follow-up and fetal chromosome testing when necessary.
In recent years, the application of SNP-array technology has greatly improved the detection rate of prenatal diagnosis of chromosomal abnormalities. Unlike traditional karyotype analysis, SNP-array can detect both micro-deletions and micro-duplicates less than 5 Mb and uniparental disomy (UPD). In our study, 9 cases had CNVs in the genome and only 1 case was missing a large segment. We observed 1 case missing a large fragment combined with a micro-deletion. The remaining 7 cases had submicroscopic chromosomal aberrations which were not detected by karyotype analysis. Among them, only 2 were likely to be benign and inherited from parents, 2 were VUS, and the remaining 3 CNVs were reported as clearly or likely pathogenic. SNP-array proved to be a necessary and effective supplement to prenatal diagnosis. Chromosome micro-array analysis technology should be the preferred diagnostic method for genetic testing, even when fetal abnormal soft markers or other structural abnormalities can be detected by prenatal ultrasound [28–30].