In our study, we described three rare prenatal cases with pure 19q microduplications involving 19q13.42, ranging from 147 kb to 1.445 Mb, which presented no structural abnormalities in sonographic examination. Case 2 was proved to get the 19q13.42 duplication from the healthy mother. To the best of our knowledge, just five cases with prenatally diagnosed trisomy 19q had been described before, and only one case was involved in 19q microduplication. Currently, there is a lack of prenatal manifestations about this chromosomal microscopic imbalance. In our study, all fetuses with various 19q duplicated loci showed no structural anomalies in pregnancy, which were different from previous trisomy 19q cases and enriched the clinic phenotypes of 19q microduplication.
Trisomy 19q, could be regarded as a recognizable syndrome and associated with a wide spectrum of clinical phenotypes, including growth and psychomotor retardation, intellectual disability, low birth weight, microcephaly, short neck, heart malformations, skeletal anomalies, genitourinary anomalies, gastrointestinal defects, seizures and facial dysmorphisms (receding forehead, ptosis, hypertelorism,flat nasal bridge, small nose, short philtrum, down turned mouth, ear anomalies) [4,11,12]. Most trisomy 19q cases also carry monosomy of another chromosome, which makes it difficult to establish a clear phenotype-genotype correlation. Till now, only 19q12-q13.2 duplication is recognized as an obesity-related syndrome with intellectual disability and minor facial findings .
Pure 19q duplications, as a rare chromosomal anomaly, can be usually discovered in live borns by molecular genetic technique .To better interpret 19q duplication, we made a summary on clinic data observed in postnatal and prenatal cases with pure 19q duplication according to literature review, as shown in Table 1 [1-4,6,11,14-23]. The age of these cases ranged from new born to 39 years. Most trisomy 19q cases (11/19) could be detectable by traditional cytogenetic analysis, with the remainder (8/19) with 19q microduplication identified through molecular cytogenetic techniques. All cases varied in size, ranging from 25 kb to 12.4 Mb, were associated with various loci in 19q. Among these duplications, 12/19 cases were de novo, 5/19 cases were parentally inherited, and 2/19 cases were not available. The incidence rate of clinical presentations were as follows: Craniofacial dysmorphism (10/19), development delay (7/19), psychomotor retardation (7/19), brain anomaly (5/19), cardiac malformation (4/19), anomalies of urinary tract (3/19), skeletal anomaly (3/19), obesity (2/19), language disorders (2/19). The deformities of the face and head were the most typical clinic manifestations: ears anomaly (8/19), macrocephaly or microcephaly (6/19), short neck (5/19), nose anomalies (4/19). In addition, some rare anomalies, such as bilateral pronator syndrome, systemic-onset juvenile idiopathic arthritis, Duane retraction syndrome type III and autism spectrum disorder, could also be observed in 19q duplication cases. Generally speaking, postnatal cases usually presented a variety of clinical features with high specificity characterized by growth/psychomotor retardation and craniofacial dysmorphism. It was noteworthy that only five cases were prenatally detected, presenting various degrees of fetal abnormalities [3,4,11,21,22]. However, our cases showed no fetal structural anomalies, which indicated that prenatal trisomy 19q cases might exhibit normal or abnormal ultrasound findings. Although the infants (cases 1 to 3) are now in healthy state, long term follow up analysis is still necessary to confirm whether there will be other emerging clinical symptoms or developmental-behavioral disorders.
To elaborate diverse clinical phenotypes, we also made detailed comparisons of cases harboring 19q13.42 microduplication in DECIPHER and ISCA databases (Fig. 1). Six cases overlapping similar duplicated regions with cases 1 and 2 were recorded. The proportions of pathogenicity were as follows: likely pathogenic (1/6) and uncertain (5/6). The incidence rate of clinical features were as follows: Development delay (3/6), intelligent disability (3/6), and autism (2/6). Seven cases involving similar duplication with case 3 were described in the databases. The clinic pathogenicity in this duplicated locus was uncertain. Only one patient nssv 13649225 presented failure to thrive, hemolytic anemia, short stature and spherocytosis, while no evident phenotypes were observed for other six cases. Generally speaking, more evidence should be accumulated to explore the pathogenicity of 19q13.42 microduplication.
Dosage-sensitive genes with genome alteration would result in phenotypic effects and be associated with human diseases, including heart disease, cancers, diabetes, neuropsychiatric disorders and others . Morbid genes in the region of 19q13.42q13.43 duplication involved in our cases were listed in Table 2. According to the ClinGen database, there are no available evidences that support the triplosensitivity of these genes. Based upon the published literature and public databases, we delineated the potentially pathogenic genes according to their functions and implications to predict the postnatal health conditions for these cases in future.
All CNVs detected in our case 1 and case 2 shared similar 19q13.42 microduplication, encompassing part NLRP12 gene (OMIM 609648; chr19: 54165218-54321990). NLRP12 gene, also known as RNO, PYPAF7, and Monarch-1, encodes the protein of NLRP superfamily, which is implicated in the activation of proinflammatory caspases and hyperproduction of interleukin-1β . NLRP12 plays critical roles in the regulation of NF-κB signaling, inflammasome activation, dendritic cell migration, and transcription of MHC class I genes . The mutations in NLRP12 have been associated with familial cold autoinflammatory syndrome-2 (FCAS2; OMIM 611762), which displays autosomal dominant inheritance. This syndrome can be induced after exposure to cold and characterized by skin urticaria, arthralgia, conjunctivitis, musculoskeletal symptoms, deafness, lymphadenopathy, and abdominal pain, most of which are accompanied by recurrent fever and serologic evidence of inflammation [27,28]. Till now, there are no related reports on NLRP12 duplication in clinic. However, Galozzi et al.  proposed that evolutionary duplication of this gene can have a causative role in autoinflammatory diseases development. Hence, we suggested that these two infants should be followed up regularly on growth and health conditions, especially for autoinflammatory diseases.
In addition, the CMA detected a 19q13.42q13.43 duplication for case 3 , containing 19 OMIM genes. This locus comprises several NLRP (Nucleotide-binding oligomeriztion domain, Leucine rich Repeat and Pyrin domain) family members. NLRP4 is mainly responsible for the inhibition of NF-κB signaling, negative regulation of RLR signaling, autophagy inhibition. NLRP5 is related to the regulation of caspase activation, apoptosis in injured neurons, and embryonic development. The functions of other members (NLRP8, -9, -11, -13) still need to be further investigated [19,26]. As is known, the zinc finger proteins (ZNFs) are the largest transcription factor family in human genome, which contain finger-like protrusions and play critical roles in physiological and pathophysiological mechanisms . Previous research showed that duplications of zinc finger genes commonly occurred during the evolution . The detected duplicated locus in case 3 included ZNF580, -444, -582, -667, -71. Research on the functions of these genes are rare. According to OMIM database, the variations in ZNF582 gene might be associated with intellectual disability, which has yet to be confirmed. ZNF580 is supposed to be involved in endothelial cell proliferation and migration. Enhancing expression of ZNF667 can inhibit the apoptosis via inhibiting Bax and Fas expression. And ZNF667 might be a new oncogene in human hepatocellular carcinoma as a new therapeutic target through enhancing BCL-2 and decreasing BAX expression. Till now, no evidence supported these genes had much relevance to our subject.
In our study, the young ages of our cases and the lacking of comparable individuals limit the assessment of growth and development in future. So long-term follow up analysis should be guaranteed till adulthood. In addition, phenotypic diversity, incomplete penetrance, and the inheritance might be associated with the clinic pathogenicity of 19q microduplication to different degrees, which needs further evidence to illustrate.
In our study, we described three rare prenatal cases consisting of 19q microduplication, encompassing 19q13.42 locus. They presented no ultrasound structural anomalies, which enriched the phenotypic spectrums of 19q duplication. It is believed that more trisomy 19q cases with clinic manifestations and molecular genetic characterization would help to refine clear genotype-phenotype correlations. For prenatally detected 19q duplications, long term follow up should be guaranteed till adulthood to confirm whether there will be other clinical symptoms and developmental-behavioral disorders afterwards.