3.3. Chromosomal Structural Abnormalities and Pathogenic Copy Number Variants
In additional to common aneuploidies, structural chromosome abnormalities were detected in four cases by karyotyping and pCNV were detected in five cases by aCGH (Table 3).
Parental chromosome analysis was always recommended and performed for prenatal cases with a structural chromosome abnormality. Apparently balanced translocations were noted in case 14 with a paternal t(4;19)(q25;q13.3), in case 15 with a de novo t(6;17) (p21.1;q24), and in case 16 with a de novo t(9;21)(p23;q21). Case 17 had a derivative chromosome 5 from a maternal t(5;7)(p15.3;q21.1) and therefore showed a segmental deletion of 5p15.3-pter and duplication of 7q21.1-qter.
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Case 18 was a male fetus with a 6.532 Mb duplication at 7p12.1-p11.2 (51,277,556-57,809,908) detected by aCGH, and this interstitial duplication was confirmed by karyotyping on cultured villus cells. This duplication includes the COBL, POM121L12, HPVC1, VSTM2A, SEC61G, EGFR, VOPP1, FKBP9L, U6, CO9, SEPT14, ZNF713, MRPS17, GBAS, PSPH, CCT6A, SUMF2, PHKG1, CHCHD2, NUPR1L, ZNF479, TRNA, and ZNF716 genes. Among genes within this duplication, three have entries in the Online Mendelian Inheritance in Man (OMIM, https://www.omim.org/). Mutations in the EGFR gene cause autosomal recessive neonatal inflammatory skin and bowel disease-2 (NISBD2, OMIM#616069) and lung cancer (OMIM#211980). Mutations in the PSPH gene cause autosomal recessive phosphoserine phosphatase deficiency (PSPHD, OMIM#614023). Heterozygous mutation in the CHCHD2 gene may be a rare cause of autosomal dominant Parkinson disease 22 (PARK22, OMIM#616710). Maternally inherited duplication, dup(7) (p11.2p12), was reported in a family with three carriers showing mild cognitive deficit [15]. The duplication at 7p12.1-p11.2 observed in this fetus was a likely pCNV. Follow up aCGH analysis on both parents revealed a paternal origin of this pCNV. The father had a history of hypertrophic cardiomyopathy and his brother died suddenly at age 26. The fetus was noted to have increased nuchal translucency by prenatal ultrasound scan and was born at term. Physical examination at three-months of age appeared well-developed except for mild plagiocephaly. His echocardiogram showed small mild muscular atrial and ventricular septal defects.
Case 19 showed a normal female karyotype by chromosome analysis on cultured amniocytes but aCGH detected a 2.488 Mb deletion at 17p13.3-p13.2 (1,078,112-3,566,410). This deletion includes the YWHAE and PAFAH1B1 genes. A reflex FISH analysis confirmed the deletion of PAFAH1B1 gene. Deletions at 17p13.3 cause autosomal dominant Miller-Dieker Lissencephaly syndrome (MDLS, OMIM#247200). Deletions involving the YWHAE gene showed significant growth restriction, cognitive impairment, and shared craniofacial features, including tall vertex, prominent forehead, broad nasal root, and epicanthal folds; deletions involving the PAFAH1B1 gene presented with seizures, significant developmental delay, and classic lissencephaly [16]. Postnatal FISH test confirmed the deletion at 17p13.3-p13.2. Clinical evaluation showed infantile spasms, seizures, and lissencephaly. The baby died at one-year of age.
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Case 20 was detected with a derivative chromosome 22 from a paternal t(16;22) (p12.2;q13.31) by chromosome analysis on cultured villus cells; aCGH defined a 22.549 Mb duplication of 16p13.3-p12.2 and a 6.688 Mb deletion of 22q13.31-q13.33. A reflex FISH analysis detected a deletion involving the SHANK3 gene at 22q13.3. This terminal 22q13.3 deletion causes Phelan-McDermid syndrome which is characterized by neonatal hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech, autistic behavior, and minor dysmorphic features (OMIM#606232). The parents decided to terminate this pregnancy.
Case 21 had a normal male karyotype by chromosome analysis on cultured amniocytes and a 2.131 Mb deletion at 22q11.21 (18,894,835-21,025,713) detected by aCGH. A reflex FISH test was performed using dual color probes for the TBX1 gene at 22q11.21 and the SHANK3 gene at 22q13.3. An abnormal pattern with a loss of the TBX1 signal in one chromosome 22 was noted in all 25 metaphases examined. Recurrent deletions at 22q11.21 cause DiGeorge syndrome (OMIM#188400). The baby was delivered at 35 weeks and found micrognathia, ASD, VSD, esophageal atresia, and tracheoesophageal fistula at birth. He had a prolonged stay at newborn intensive care unit (NICU) with a surgery repair of ASD, VSD, and tracheoesophageal fistula. A follow up echocardiogram at 3-months of age showed an excellent repair with no atrial level shunt, a small residual, pressure and volume restrictive VSD, and adequate biventricular function.
Case 22 had a normal female karyotype by chromosome analysis on cultured amniocytes and a 2.834 Mb duplication at 22q11.21-q11.23 (21,808,950-24,643,108) detected by aCGH. A reflex FISH test was performed using dual color probes for the ABL1 gene at 9q34.1 and the BCR gene at 22q11.21. Of the 200 interphase cells examined, 100% showed two signals for the ABL1 probe and three signals (one independent and two twin-spot like) for the BCR probe. This result confirmed the 22q11.21-q11.23 duplication. Duplications of 22q11.21-q11.23 distal to the 22q11.21 microdeletion syndrome region have been identified in familial and de novo cases; the patients showed variable development delay with no speech or walking, and other neurological features vary from normal to profound hypotonia and/or severe seizures and some contradicting features like macrocephaly and microcephaly [17]. The fetus was noted to have a mildly hypoplastic right ventricle by prenatal ultrasound scan. She was born at term and remained in the NICU for eight days with required intermittent O2. A follow up echocardiogram at 7-months of age showed resolved bilateral peripheral pulmonary artery stenosis and small ASD with mostly left to right flow.
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