PMC8362598_01
Facial features and limb malformations of the fetus in case 1. A 28-year-old Chinese woman was referred for prenatal diagnosis at 16 weeks of gestation due to fetal nuchal translucency (NT) thickening (A). The pregnancy was terminated at 20 weeks, and autopsy showed distinct facial features (B, C) and limb defects (B, D, and E) in the fetus as indicated by the arrows.
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F1
A 28-year-old Chinese woman, gravidity 1, parity 0, was referred to our institution for prenatal diagnosis at 16 weeks of gestation due to fetal nuchal translucency (NT) thickening (NT, 4.8 mm; crown-rump length: 58 mm) as detected by ultrasound examination at 12 weeks and 3 days of gestation (Figure 1A). SNP array in family trios revealed a de novo heterozygous microdeletion of 0.2 Mb at chromosome 5p13.2 [arr[1GRCh37]5p13.2 (36848530_37052821) x 1] in the fetus (Supplementary Figure 1). The distinctive facial features and limb malformations of the male fetus were documented at autopsy (case 1 in Table 1; Figure 1), which support a diagnosis of classic CdLS (Supplementary Table 1) in terms of the clinical classification guidelines (Kline et al.,).
Facial and limb features of the newborn and Sanger sequencing results of NIPBL c.5566A>G mutation in case 2. The newborn presented with low hairline, hypertrichosis of the eyebrows, broad depressed nasal bridge, smooth long philtrum with thin lips (A), and single palmar crease (B). Sanger sequencing validated the de novo c.5566A>G mutation in the newborn (C).
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F2
A non-synonymous variant in NIPBL (NM_133433.4: exon29: c.5566A>G: p.R1856G) was identified by using WES, and this de novo variation was further confirmed by using Sanger sequencing (Figure 2C).
PMC8362598_02
Facial and limb features of the newborn and Sanger sequencing results of NIPBL c.5566A>G mutation in case 2. The newborn presented with low hairline, hypertrichosis of the eyebrows, broad depressed nasal bridge, smooth long philtrum with thin lips (A), and single palmar crease (B). Sanger sequencing validated the de novo c.5566A>G mutation in the newborn (C).
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F2
A non-synonymous variant in NIPBL (NM_133433.4: exon29: c.5566A>G: p.R1856G) was identified by using WES, and this de novo variation was further confirmed by using Sanger sequencing (Figure 2C).
Clinical features of the proband and Sanger sequencing results in case 3. The proband (A, II: 1) presented with typical facial features of Cornelia de Lange syndrome (CdLS) and upper limber defects (B-E). The (F) panel shows the Sanger sequencing results of NIPBL c.448dupA mutation in the family.
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F3
The index patient (an 8-month-old girl) was the first child of the first pregnancy of a healthy non-consanguineous Chinese couple with no remarkable history in genetic diseases (Figure 3A). The proband in case 3 had typical facial features of CdLS (Figures 3B,C; Table 1) with limb defects (Figures 3D,E), being classified as classic CdLS (Supplementary Table 1). WES in the family trios identified a de novo frameshift variant of NIPBL (NM_133433.4: exon 5: c.448dupA: p.S150Kfs*23) in the proband, which was validated by Sanger sequencing (Figure 3F). Sanger sequencing with genomic DNA from amniocytes showed that the c.448dupA mutation was not present in the fetus of the second pregnancy of the couple (Figure 3F).
PMC8362598_03
Clinical features of the proband and Sanger sequencing results in case 3. The proband (A, II: 1) presented with typical facial features of Cornelia de Lange syndrome (CdLS) and upper limber defects (B-E). The (F) panel shows the Sanger sequencing results of NIPBL c.448dupA mutation in the family.
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F3
The index patient (an 8-month-old girl) was the first child of the first pregnancy of a healthy non-consanguineous Chinese couple with no remarkable history in genetic diseases (Figure 3A). The proband in case 3 had typical facial features of CdLS (Figures 3B,C; Table 1) with limb defects (Figures 3D,E), being classified as classic CdLS (Supplementary Table 1). WES in the family trios identified a de novo frameshift variant of NIPBL (NM_133433.4: exon 5: c.448dupA: p.S150Kfs*23) in the proband, which was validated by Sanger sequencing (Figure 3F). Sanger sequencing with genomic DNA from amniocytes showed that the c.448dupA mutation was not present in the fetus of the second pregnancy of the couple (Figure 3F).