Neuromegen: Achieving rapid diagnosis for neurodevelopmental disorders

Abstract

Background: Whole-exome sequencing (WES) is a clinical diagnostic and research tool designed to identify and classify the arrangement of all protein-coding nuclear genes in the genome. Cases of infertility and recurrent miscarriages complicated by multiple-loop consanguinity may benefit from the implementation of whole-exome sequencing. Case presentation: We report a case of a Kuwaiti consanguineous couple referred to the genetics department with a history of three live births followed by fourteen miscarriages, most of which occurred during the third and fourth months of gestation. The initial routine investigations including the blood tests, thyroid function, imaging, immunological and antibody profile, and chromosomal microarray of both parents were normal. The presence of multiple loops of consanguinity made making a correct diagnosis difficult. The option of whole-exome sequencing to examine the entire exome of both parents was proposed. After taking the patients’ consent, the WES results of the couple revealed them both to be carriers of a previously unreported heterozygous variant of the CEP57 mutation resulting in multiple pregnancies with type 2 mosaic variegated aneuploidy that were incompatible with life. Methods: Whole-exome sequencing was agreed by the treating clinical geneticists as a suitable option to identify the presence of a possible genetic mutation. The age, gender, ethnicity, medical history, family history, consanguinity, laboratory investigation results, clinical interpretation and implication of the results have been documented. Conclusion: The reported case of infertility and recurrent miscarriages associated with multiple-loop consanguinity showed no abnormalities using conventional diagnostic methods. The application of whole-exome sequencing for the couple revealed them to be carriers for the type 2 mosaic variegated aneuploidy syndrome gene CEP57. In cases of multiple-loop consanguinity, whole-exome sequencing should be considered to aid in the diagnosis of the genetic mutations. Introduction Mosaic variegated aneuploidy (MVA), also known as WarburtonAyane-Yeboa Syndrome, is classified by the Genetic and Rare Diseases (GARD) of the National Institute of Health (NIH) as a rare disease and has an autosomal recessive mode of inheritance [1]. MVA is classified into 2 types, MVA type 1 caused by BUB1B gene mutation and MVA type 2, which is less common and is caused by CEP57 gene mutation. Both types, however, result in defective chromosome separation during cell division [1]. The CEP57 gene plays a role in the stability and organization of cell spindle microtubules during cell division [2]. After the cell has duplicated the chromosomes, the spindle microtubules attach to the copies and pull them to opposite poles of the cell, ensuring that each new cell has one complete set of chromosomes; in MVA this organized separation does not occur resulting in mosaicism [2-4]. The CEP57 gene has also been linked to the transport of fibroblast growth factor 2 (FGF2), a signaling protein that regulates the development and growth of cells, along microtubules [2,5]. MVA is characterized by aneuploidy, most commonly presenting as monosomies or trisomies in cells. Due the random nature of the syndrome, the presentation varies from one case to the next. However, the most common features of MVA include intrauterine growth retardation (IUGR), microcephaly, brain abnormalities, and morphological anomalies such as low set ears and a broad nasal bridge [2,3]. Additionally, MVA has been associated with certain malignancies such as rhabdomyosarcoma, leukemias, and Wilms tumor.1 Case presentation A married couple, a 38-year-old Kuwaiti woman and her husband, were referred to the genetics department by their treating gynecologist due a series of multiple and unexplained miscarriages. The couple have been in a consanguineous marriage (first degree paternal cousins) for the past 15 years. The husband was assessed to be healthy and had no significant past medical history. The wife was known to have hypothyroidism which was well-controlled and was being treated with eltroxin 100 mcg, she follows-up regularly with her endocrinologist. Her obstetric history revealed the wife to be G17 P3 T2 A14 L2. The first two pregnancies were one year apart, both pregnancies were full-term, healthy girls with no complications. The third pregnancy produced a premature male diagnosed with Dandy-Walker syndrome. He died at 2 and a half years of age because of medical complications related to his condition. No DNA was obtained. The subsequent twelve pregnancies ended in miscarriage, all occurring in the third and fourth *Correspondence to: Munirah T Aljaser, Farwaniya Hospital MOH, Kuwait, Tel: 96551379990, E-mail: m.t.aljaser@gmail.com Received: June 08, 2018; Accepted: June 20, 2018; Published: June 25, 2018 Aljaser MT (2018) The use of whole exome sequencing to identify carriers of Mosaic Variegated Aneuploidy (MVA): A case study Volume 5(3): 2-5 Integr Mol Med, 2018 doi: 10.15761/IMM.1000332 months of gestation. No tissue was karyotyped, and no DNA was banked from any of the fetuses. The sixteenth pregnancy was revealed by ultrasound to be a female fetus with severe cardiac and neurological anomalies. The patient miscarried in the fourth month of gestation and no DNA was obtained. The seventeenth pregnancy was also a female fetus with severe cardiac anomalies and was miscarried in the fourth month of gestation. No DNA was obtained. The couple underwent full laboratory investigations. All of the investigations of the wife (Table 1) and husband (Table 2) came back normal. Due to the couples’ lineage being complicated by multiple loops of consanguinity, and their normal karyotype and chromosomal microarray results, it was decided that whole exome sequencing (WES) would be a suitable option for the couple to help reach a correct, and accurate diagnosis. The couple was counselled about the advantages and disadvantages of WES and they agreed to have proceed with the investigation. The WES revealed that both the husband and the wife were carriers of mosaic variegated aneuploidy genes CEP57. Chromosome Analysis and peripheral blood using G-banding technique: Banding: G Chromosome number: 46 Autosomes: normal Sex Chromosomes: XX Mutation screening: Screening for G1619 à A mutation in factor V Leiden G20210 à A mutation in prothrombin genes. The patient is not a carrier of any of the above-mentioned mutations. Hematology: PT INR (ACT TOP 500) 1.08 0.88-1.13 INR *PT Patient 15.5 13-16 seconds *APTT Patient 32.6 26-34.4 seconds *APTT Ratio 1.09 0.87-1.13 (Ratio) PROTEIN S ACTIVITY 93.8 63.5-149 % CBC: WBC 5.8 4.1-11.2 109/L RBC 4.12 3.83-5.08 1012/L HEMOGLOBIN 119 117-155 g/L HEMATOCRIT 0.361 0.345-0.463 L/L MCV 87.6 80.4-95.9 fL MCH 28.8 27.2-33.5 pg MCHC 329 325-352 g/L RDW 13.5 11.7-14.6 % PLATELET COUNT 279 150-410 109/L