Mixoploidy combined with aneuploidy in a 13 year‐old patient with severe multiple congenital abnormalities and intellectual disability

Abstract

We report on a 13-year-old female patient, born from healthy, non-consanguineous parents. She was born at 37 weeks gestation by cesarean section because of meconium stained amniotic fluid and late fetal heart decelerations. After birth she required assisted ventilation because of respiratory insufficiency. During intubation a posterior mucosal cleft palate and bifid uvula were noted. She was small for gestational age (weight 1,780 gram, −3 SD; head circumference at −1.2 SD) and showed dysmorphic features with frontal bossing, rethrognatia, hyperplastic gums, large fontanelles, single transverse palmar creases, ulnar deviation of wrists, bilateral clubfeet and syndactyly of toes 1-5th. No cardiac or other visceral abnormalities were detected.In time, developmental milestones were delayed. Her growth rate was also delayed and at the age of 6 years ( Figure 1a) height followed the −4 SD, with an average head circumference for the age. Examination at age 6 years showed metopic synostosis, high-arched eyebrows, flattened orbital ridges, small chin, prominent front teeth, short philtrum, congenital contractures of fingers, elbows and knees (Figure 1b), broad thorax with widely separated nipples (Figure 1c), thoracic scoliosis, high-pitched voice, nasal speech and hypotonia. Failure to thrive required gastric tube feedings. She also presented with mild-moderate intellectual disability. Brain MRI at 4 years showed a retrocerebellar arachnoidal cyst and thin corpus callosum. Metabolic screening shortly after birth was normal. Because she displayed mild features resembling Bohring-Opitz trigonocephaly, the ASXL1 gene was analyzed by capillary sequencing of the coding regions in DNA extracted from blood. No pathogenic variants in this gene were detected. G-banded chromosome analysis shortly after birth revealed a 45,X complement in peripheral blood, consistent with Turner syndrome. As the girl's phenotype could not be explained by this Turner karyotype, additional genetic analyses were performed. Subtelomeric MLPA (SALSA P036C en P070 kits, MRC Holland) and genomic array (Affymetrix 250 k Nsp1 array) analysis using DNA obtained from peripheral blood confirmed the 45,X karyotype.Additionally, array showed a small variant of unknown significance, inherited from the healthy father (114 kb interstitial loss on chromosome 4q31.22, containing part of the glycophorin E and B genes).As still no satisfactory explanation for the girl's phenotype was found, a mosaic genetic aberration was suspected. Therefore, genomic array was repeated on the Illumina HumanCyto12-SNP array using DNA obtained from a skin biopsy. An abnormal profile was observed, suggesting the presence of a triploid cell line with loss of one X chromosome. Based on the B-allele frequency, this cell line could possibly be present in a high mosaic form, that is, in more than 75% of the cells (Figure 2a). Subsequent karyotyping on cultured skin fibroblasts indeed showed a mosaic karyotype: 68,XX[5]/45,X[1] (Figure 2b), confirming the array findings.In conclusion, the pat...

Genome‐wide abnormalities in embryos: Origins and clinical consequences

“…88 Additional chromosome aneuploidies were also reported in some patients with 2n/3n mixoploidy. [89][90][91][92][93] In these patients, the peripheral blood lymphocytes are usually diploid and the triploid cell lineage is uncovered by fibroblast analysis. Whether tissue specificity is a consequence of selective elimination of triploid lineage during cellular differentiation remains to be determined.…”

“…While full triploidy is largely incompatible with life, diploid/triploid mosaicism has been well documented in children and young adults, 82‐87 including an 8‐year‐old girl, conceived via assisted reproduction using ICSI 88 . Additional chromosome aneuploidies were also reported in some patients with 2n/3n mixoploidy 89‐93 . In these patients, the peripheral blood lymphocytes are usually diploid and the triploid cell lineage is uncovered by fibroblast analysis.…”

Human RAD50 deficiency: Confirmation of a distinctive phenotype

“…G‐banded chromosome analysis was performed according to routine standard procedures and genomic arrays were performed as previously described (van Zutven et al, 2018). DNA was isolated by standard procedures from blood leukocytes.…”

Programmatic Detection of Diploid-Triploid Mixoploidy via Whole Genome Sequencing

“…One type of whole chromosomal mosaicism is diploid-triploid mosaicism (DTM) or 2n/3n mosaicism, in which individuals have a percentage of triploid cells with 69 chromosomes in addition to diploid cells [10,11,12,13]. In contrast to patients with full triploidy, which occurs in approximately 1% of all conceptions and almost always results in early spontaneous abortion, patients with mixoploidy can survive the neonatal period and in some cases live to adulthood [11,12,14].…”