A case of penta X syndrome caused by nondisjunction in maternal meiosis 1 and 2

Prenatal phenotype

The pregnancy was uneventful until gestational age (GA) week 28. No abnormalities were detected at the ultrasonographic examination at GA week 13+1 and at the prenatal anomaly scan at GA week 20. At GA week 28, polyhydramnios was detected during a routine midwife appointment. Regular fetal ultrasonographic examinations from GA week 28 until delivery revealed polyhydramnios, dilated intestines, IUGR with −23.1% to −30.7% weight deviation, and short femora (−2.8 SD). Because of suspected brain sparing, the birth was initiated at GA week 38+3.

Postnatal phenotype

The newborn girl had a birthweight of 2484 g, a length of 48 cm, and a head circumference of 34 cm. She had hypertelorism, abnormal configuration of the ears, cleft palate (in the soft palate), bilateral single transverse palmar creases, bilateral clinodactyly of the fifth finger, short lower limbs compared to the rest of the body, mild hypotonia, and a shrill animal-like cry. Echocardiography showed mild stenosis of the right pulmonary artery and mild coarctation of aorta, none of which were thought to have clinical significance. Ultrasonography of the brain showed hypoplasia of the corpus callosum, and the brain parenchyma appeared slightly more echogenic than normal. Furthermore, a few subependymal pseudocysts were observed on the right side and a single subependymal pseudocyst was observed on the left side. All findings by ultrasonography of the brain were of unknown clinical significance. Based on the clinical impression, there was initially no need for further follow-up. No structural eye abnormalities were found at examination by ophthalmologist. Ultrasonography of the urinary tract did not reveal any abnormalities. The girl was discharged when she was 17 days old still requiring enteral tube feeding as a supplement to bottle feeding because of feeding difficulties and failure to thrive. Close follow-up was planned. The patient's clinical features are summarized in Table 1.

Chromosome analysis

Standard chromosome analysis with Q-banding was performed on cultured peripheral blood lymphocytes from the patient and revealed the karyotype 49,XXXXX in all 10 examined metaphases.

Aneuploidy screening

Standard aneuploidy screening QF-PCR analysis for chromosomes 13, 18, and 21 as well as the sex chromosomes was performed on DNA extracted from a peripheral blood sample from the patient. The results showed a triallelic Pentasomic pattern in 2 of 3 markers on the X chromosome. The third marker was borderline within normal range.

SNP-array and genotyping analysis

To clarify the pathogenesis of penta X syndrome, SNP-array analysis (Illumina CytoSNP-12 v2.1 format; standard protocol) followed by genotyping analysis of the data (Illumina Genomestudio v2011.1 and Microsoft Excel 2010) was performed on DNA extracted from the patient and her parents.

SNP-array data are given as B-allele frequencies (BAF) with a value between 0 and 1 representing the observed frequency of single nucleotide polymorphisms (A or B alleles). To perform genotyping analysis, the BAF must be translated into genotype data. The SNP-array data from the patient showed six different BAF groups for the X chromosome, corresponding to the genotype: AAAAA, AAAAB, AAABB, AABBB, ABBBB, BBBBB (5 X chromosomes; Fig. 1A and B). The observation of six different BAF groups confirmed the diagnosis of penta X syndrome. The SNP-array data from the mother showed three different BAF groups for the X chromosome, corresponding to the genotype: AA, AB, BB (2 X chromosomes). The SNP-array data from the father showed two different BAF groups for the X chromosome, corresponding to the genotype: A or B (1 X chromosome). These observations confirmed a normal X chromosome constitution for both parents.

To investigate how many of the patient's X chromosomes that were of paternal origin, we identified SNPs with opposite parental genotypes. Thus, SNPs where the father's genotype was A and the mother's genotype was BB, as well as SNPs where the father's genotype was B and the mother's genotype was AA, were identified. If the father's genotype was A, the number of A in the patient's genotype revealed how many copies of the father's X chromosome the patient had inherited. Our analysis showed that opposite parental genotypes were observed in 822 cases. In 818 of these 822 cases, the patient's genotype showed ABBBB or AAAAB. The result indicates that only one of the patient's X chromosomes was inherited from the father.

In conclusion, our genotyping results show that the patient's penta X syndrome was caused by duplication of both homologue maternal X chromosomes.

STR-marker analysis

To confirm the genotyping results, STR-marker analysis (Elucigene QST*Rplusv2; standard protocol) was performed on DNA extracted from the patient and her parents. The analysis included 11 polymorphic STR-markers spread on the sex chromosomes and one nonpolymorphic sex chromosome-specific marker. Comparison of the results of the patient and the parents showed, in two loci with informative distribution of alleles, that one allele was inherited from the father and four alleles were of maternal origin, with two alleles from each of the X chromosomes of the mother (Fig. 2). In five loci, the distribution of the alleles was compatible with the same inheritance pattern. The remaining five loci were noninformative. The STR-marker analysis could thereby confirm that the patient's penta X syndrome was caused by duplication of both homologue maternal X chromosomes.