Mosaic variegated aneuploidy syndrome caused by a CEP57 mutation diagnosed by whole exome sequencing

Key Clinical Message This case highlights an important lesson for laboratory genetic testing. Geneticists and Genetic Counselors should be aware that although rare, mosaic variegated aneuploidy should be considered if mosaic aneuploidies are observed on karyotype, particularly in the context of short stature.


| INTRODUCTION
Mosaic variegated aneuploidy (MVA) syndrome is a rare disorder presenting with short stature, intellectual disability, and mosaic aneuploidies. Herein, we report a patient with MVA diagnosed via whole exome sequencing after two normal karyotype results. MVA should be considered if mosaic aneuploidies are observed on karyotype.

| CLINICAL REPORT
The patient was an 11-year 6-month-old Pakistani female who presented for an initial endocrine evaluation of short stature. She was born at 38 weeks of gestation to consanguineous parents. She had past diagnoses of IUGR, failure to thrive, developmental delay, mild ID, acanthosis nigricans, and precocious puberty. A physician in Pakistan treated her with leuprolide depot, growth hormone, and metformin for precocious puberty, idiopathic short stature, and acanthosis nigricans, respectively. Her physical examination revealed a prominent forehead and nose, frontal bossing, triangular face, and mild rhizomelic shortening of upper limbs. Her height was 51 inches (<3rd percentile), weighed 76 lbs (19th

| MOLECULAR ANALYSIS
Informed consent was obtained from the parents and approved by the local institutional review board prior to molecular analysis. Based on the family history of consanguinity and unaffected parents, we suspected an autosomal recessive pattern of inheritance for which we performed WES. We hypothesized that the causal variant would be a rare, nonsynonymous, or frameshift homozygous variant. We excluded all variants with a minor allele frequency (MAF) >0.001 in the 1000 Genomes database (www.1000genomes.org) or in our internal exome database. There were 34 homozygous variants that fit these criteria. Review of each identified gene revealed only one that has previously been associated with growth retardation. This variant is a frameshift mutation in CEP57 (c.697delA, p.Lys235Argfs*31) and is not listed in dbSNP or ClinVar but is present in the Exome Aggregation Consortium database (exac.broadinstitute.org) with a MAF of 2.576e −5 . Truncating mutations in CEP57 have been reported to cause MVA (OMIM 614114). 2,3 Sanger sequencing of CEP57 in the patient and her parents confirmed that the patient had this homozygous frameshift mutation, while her parents each had a heterozygous frameshift mutation (Figure 1).
Due to WES findings, we ordered a repeat karyotype from peripheral blood mononuclear cells. Surprisingly, the results from the clinical laboratory were normal 46,XX. After requesting a re-review, 17 of 22 cells were 46,XX, while 5 cells had unique aneuploidies that the laboratory initially interpreted as artifacts (Figure 2). The mosaic aneuploidies confirmed the diagnosis of MVA. homozygous mutations in BUB1B or TRIP13 is associated with an increased risk of cancer, but it is unknown if MVA caused by mutations in CEP57 is associated with increased cancer risks. [1][2][3]7,10 Had this been known, growth hormone might have not been prescribed. Consistent with prior reports of MVA caused by mutations in CEP57, this patient has growth retardation, IUGR, ID, rhizomelic limb shortening, and skull anomalies (temporal bossing and triangular face) ( Table 1). 2,3 This patient also has precocious puberty and acanthosis nigricans, which may be previously undescribed features of MVA or may be unrelated to this syndrome.

| DISCUSSION
Additional case reports of patients with MVA caused by mutations in CEP57 are needed to further define the phenotypic spectrum.
This report highlights an important lesson for genetic testing. Karyotype was normal (46,XX) despite the presence of mosaic aneuploidies in a subset of cells. For a chromosome gain to be considered clonal, it must be observed in at least two cells per ISCN guidelines. 11 This patient could have been diagnosed sooner had mosaic aneuploidies been detected and reported in her first karyotype. Laboratory and Clinical Geneticists should be aware that MVA should be considered if multiple mosaic aneuploidies are observed.

AUTHOR CONTRIBUTIONS
DB: analyzed WES and wrote manuscript. SE: evaluated the patient, wrote the clinical description, and edited the manuscript. AD: analyzed WES, edited, and approved manuscript.