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Study question What underlies an increased risk of having children with neurodevelopmental disorders in women with miscarriage? Summary answer Women with miscarriage have a statistically significant increase in the frequency of giving birth to children with intellectual disabilities due to CNV. What is known already A link between woman’s history of miscarriage and neurodevelopmental disorders (NDD) in her children was shown recently (PMID:30058166, PMID:33580539). In women with sporadic and recurrent miscarriage, the risk of having a child with NDD is increased by 13% and 30%, respectively (PMID:33580539). About half of miscarriage cases can be due to genetic causes. Genetic abnormalities also underlie NDD. It is likely that CNV may be a common etiological factor for both pathologies. Our aim was to assess the frequency and characteristics of CNV in groups of mothers having a child with NDD and presence or absence of miscarriages in anamnesis. Study design, size, duration Families with children with NDD and maternal obstetric history were investigated (n = 405). They were divided into groups based on the presence (n = 190) or absence (n = 215) of pathogenic CNV in a child. Further each group was divided into subgroups with the presence (n = 37, n = 21) or absence (n = 153, n = 194) of miscarriage to determine the association of CNV with pregnancy loss and NDD. Genes involved in CNVs were obtained to identify pathogenetically significant molecular pathways. Participants/materials, setting, methods The DNA of patients and their parents was isolated from blood lymphocytes. Probands with NDD were studied using aCGH on SurePrint G3 Human CGH Microarray Kit, 8 × 60K (Agilent Technologies). Validation of CNVs and determination of their origin was carried out using qPCR. Enrichment analysis was performed by the Enrichr resource and the Mammalian Phenotype ontology. The results of the analysis were considered significant at p ≤ 0.05. The chi-squared test was used for statistical analysis. Main results and the role of chance For the first time we showed that pathogenic CNVs were statistically significantly more common in families with miscarriage having a child with NDD (p = 0.006). In the groups with or without miscarriage, respectively, 16 and 66 deletions and 21 and 87 duplications were found. Thus, no predominance of a certain type of CNV was found (p = 0.991). The origin was established for 49 CNVs out of 190 (26%). The group with miscarriage included 8 maternally inherited and 2 de novo CNVs, while the non-miscarriage group included 33 inherited (mat-18, pat-15) and 6 de novo variants (p = 0.899). Enrichment analysis revealed 26 and 36 categories, respectively, in miscarriage and non-miscarriage groups. Common categories between the groups were maternal imprinting, abnormal cochlear innervation pattern, abnormal GABA-mediated receptor currents, increased skeletal muscle fiber size. Separately, the miscarriage group included one category associated with abnormal head morphology. The group without miscarriage included categories associated with development, functioning and anomalies of different organs. Although the enrichment analysis identified categories that may be associated with the pathologies included in this study, at this stage of data collection it was not possible to explain why some CNV can lead to either miscarriage or child with NDD in the same family. Limitations, reasons for caution There is no data on the causes of miscarriage, at least on the presence or absence of maternally inherited CNV in abortions. A small sample size does not allow us to identify differences in the structure of CNVs between groups with and without miscarriage. Wider implications of the findings Accumulating data potentially can be used for predicting the risk of having a child with NDD in families with miscarriage. If one of the parents carries pathogenic CNV with pleiotropic effect prenatal diagnosis or PGT-SR should be recommended. This study was supported by the Russian Science Foundation № 21-65-00017, https://rscf.ru/project/21-65-00017/. Trial registration number not applicable

IntroductionOver 20% of patients with developmental delay (DD) has copy number variations (CNV) of unknown significance. Some CNV may be associated with disease in a patient and also present in their apparently healthy parents. According to the two-hit model another CNV may contribute to phenotypic variation of such genomic disorders.ObjectivesDD diagnostics improvement.AimsUnderstanding the pathogenic significance of concomitant 3q13.31 and 22q13.32-q13.33 microdeletions.MethodsRing chromosome 22 was first detected by conventional cytogenetics. Microdeletions at 3q13.31 and 22q13.32–q13.33 were revealed by agilent technologies 60 K microarray and confirmed by qPCR. Ring chromosome was confirmed by FISH.ResultsWe present a four-year-old girl with del22q13.32-q13.33 resulted in a ring chromosome 22 and a single TUSC7 gene microdeletion at 3q13.31. The del22q13.32-q13.33 originated de novo, whereas del3q13.31 was inherited from healthy mother. The 22q13.32-q13.33 locus is associated with Phelan-McDermid syndrome (PHMDS, OMIM 606232). The patient demonstrated features both typical for the syndrome (psychomotor and speech development delay, autistic signs, aggression, sleep alteration, seizures) and atypical – attention deficit-hyperactivity disorder (ADHD), ventriculomegaly, and reduced size of cerebella hemispheres (Dandy-Walker variant). ADHD and ventriculomegaly were previously described in patients with del3q13.31 (OMIM 615433) but Dandy-Walker variant was observed in our patient for the first time. Possibly, atypical for PHMDS features, may result from trans-epistasis of microdeletions.ConclusionsMultiple CNVs in one patient complicate genotype-phenotype correlations due to possible overlapping phenotypes and/or modifying effect of variants. This study was supported by Russian Science Foundation, grant no. 16-15-10231.

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