A 23-year-old pregnant woman, G1P0 (gravida 1, para 0), was admitted to foetal medical centre. The pregnant woman was 142 cm tall, within weight in the normal range for height, as were her parents and husband. The couple had normal intellectual development and no abnormal family history or mutagenic exposures.
This pregnancy was conceived naturally. No noninvasive prenatal genetic testing (NIPT) was performed in the first trimester of pregnancy. However, sonography at 24+ weeks of gestation (w.o.g.) detected intrauterine growth retardation (IUGR), absence of nasal bone (Fig. 1A), and ventricular septum defect (Fig. 1B). Ultrasonography at 30th w.o.g. confirmed the previous findings and additionally a foramen ovale. However, at 34 w.o.g. a second ultrasound examination revealed no abnormalities at all.
Cytogenetic analysis (G-banding resolution was approximately 400–550 bands) and chromosomal microarray (CMA) were done after amniocentesis in 24+ w.o.g.. Also maternal blood sample and that of parents of the mother were cytogenetically analysed. After birth, karyotype and CMA analyses were performed again. Pre- and postnatal banding cytogenetics showed a karyotype of 46,XY,r(6)(p25q27)mat. The mother had in peripheral blood a mosaic karyotype: 46,XX,r(6)(p25q27)[44]/47,XX,r(6)(p25q27),+r(6)(p25q27)[2]/46,XX[15], and the father had a normal result as 46,XY (Fig. 2A–D). The karyotypes of the maternal grandmother and grandfather were normal (46,XX; 46,XY).
For CMA a SNP array was performed using KaryoStudio 1.4.3.0 Build 37 software (Illumina, San Diego, CA) to define possible copy number changes. Besides whole-exome sequencing (WES) was completed by the BGI Huada Gene Shenzhen Huada Clinical Testing Centre as previously reported [9]. Obtained molecular genetic data was bioinformatically analysed using DECIPHER (http://decipher.sanger.ac.uk), UCSC (http://genome.ucsc.edu), DGV (http://dgv.tcag.ca/dgv/app/home), ClinGen (http://dosage.clinicalgenome.org/), gene imprint database (http://www.geneimprint.com) and other Online-Mendelian Inheritance in Man (OMIM) databases (http://www.omim.org). Karyotype and CMA-results are described according to the International System for Human Cytogenomic Nomenclature (ISCN, 2020) [10].
CMA analyses in the foetus (amnion and peripheral blood) gave the following result: arr[GRCH37] 6p25.3(203,254_1,138,134)×1,6p25.3p25.2(1,153,042_4,172,096)×3 (Fig. 2E). In the mother the CMA-findings were: arr[GRCH37] 6p25.3(203,254_1,138,134)×1~2,6p25.3p25.2(1,153,042_4,172,096)×2~3. SNP-array confirmed the mosaic situation of 90% of the cells carrying the ring chromosome; also a isoUPD(6) mosaicism was found for 10% of the cells, explaining the 15 cells with normal karyotype 46,XX found in cytogenetics as being due to monosomic rescue.
Whole-exome sequencing confirmed the result of SNP-array as: seq[GRCh37] dup(6)(p25.3p25.2) chr6:g.1127408_4191151dup (3.06 Mb) and seq[GRCh37] del(6)(p25.3p25.3) chr6:g.63810_1127408del (1.06 Mb).
The boy was delivered by caesarean section at 39+2 weeks of gestation. Congenital dislocation of the right knee joint occurred in the newborn (Fig. 1C), even though no knee joint abnormality was observed at any stage of pregnancy. After treatment, the dislocation of the knee and limb was normal. The newborn had a birth weight too low for gestational age of 2.150 kg, and was overall in good mental condition, without any inborn defects. However, follow-up 8 months of age showed developmental delay concerning length (64 cm) and weight (5 kg); also congenital heart malformation was diagnosed by Doppler sonography as ventricular septal defect and atrial septal defect with the enlarged diameter of pulmonary artery and left heart enlargement; also the third top valve had a micro reflux and pulmonary hypertension was detected while left ventricular systolic function was normal (Fig. 1D).
Overall, as of the date of publication of this article, there have been no abnormal phenotypes in the newborn except for growth retardation and congenital heart malformations.