Discordant Semilobar Holoprosencephaly in Monozygotic Twins with de novo inv dup(15) Marker Chromosome and de novo Mutation on SHH Gene

Abstract

We present a 30-year-old woman with a twin pregnancy, 1 fetus displaying a small head circumference, semilobar holoprosencephaly, and cleft lip as detected by ultrasound at 23 weeks of gestation. Fetal magnetic resonance imaging confirmed the diagnosis of semilobar holoprosencephaly. The other twin, however, had an appropriate fetal growth, devoid of any major structural anomalies. Karyotyping by G-banding of amniocentesis specimens in both fetuses showed 47,XY,+mar. Fluorescence in situ hybridization showed in the marker chromosome positive dicentric signals for the chromosome 15 centromere-specific alpha satellite DNA probe (D15Z1) and negative signals for the SNRPN probe (15q11–13), thus establishing a cytogenetic diagnosis of 47,XX,+mar.ish idic(15)(q11–q13)(D15Z1++,SNRPN–) for both fetuses. The parental karyotypes were normal. The fetuses, therefore, had a de novo inv dup(15) marker chromosome without involvement of the Prader-Willi region. Short tandem repeat markers (total 15 markers) confirmed that the fetuses were monozygotic twins. Short tandem repeat markers at the 15q region (total 6 markers) excluded the possibility of uniparental disomy (15) mat or uniparental disomy (15) pat. Molecular study in both fetuses of TGIF, SHH, SIX3, and ZIC2 genes revealed a heterozygous 1085 C > T (Ser 362 Leu) on the SHH gene, but a homozygous 1085 C > C (Ser 362 Ser) for both parents on the SHH gene. The couple decided to terminate the pregnancy at 26 weeks of gestation. To our knowledge, this is the first report of semilobar holoprosencephaly with inv dup(15) marker chromosome and missense SHH gene mutation 1085 C > T (Ser 362 Leu).

Non‐identical monozygotic twins, intermediate twin types, zygosity testing, and the non‐random nature of monozygotic twinning: A review

“…The affected twin had a (post-zygotic) nonsense mutation in the IRF6 gene (IRF6, glu92ter), whereas the unaffected twin did not have the mutation. In contrast, a pair of MZ twins discordant for semilobar holoprosencephaly showed the same heterozygosity for a Ser362Leu in the SHH gene [Peng et al, 2007]. (3) Mutations in mitochondrial DNA (mtDNA).…”

Effect of acidic fluoride solution on β titanium alloy wire

“…The affected twin had a (post‐zygotic) nonsense mutation in the IRF6 gene (IRF6, glu92ter), whereas the unaffected twin did not have the mutation. In contrast, a pair of MZ twins discordant for semilobar holoprosencephaly showed the same heterozygosity for a Ser362Leu in the SHH gene [Peng et al, 2007]. Mutations in mitochondrial DNA (mtDNA).MZ twin brothers discordant for Leber hereditary optic neuropathy were heteroplasmic for a de novo 14484 mtDNA mutation [Biousse et al, 1997].…”

“…The affected twin had a (post‐zygotic) nonsense mutation in the IRF6 gene (IRF6, glu92ter), whereas the unaffected twin did not have the mutation. In contrast, a pair of MZ twins discordant for semilobar holoprosencephaly showed the same heterozygosity for a Ser362Leu in the SHH gene [Peng et al, 2007].…”

Successful management of discordant alobar holoprosencephaly in monochorionic diamniotic twins with normal karyotype: a case report

“…Frontal view of the fetus showing frontal bossing, hydrocephaly, hypotelorism of eyes, flat nasal bridge, macroglossia and cheilo/palatoschisis (1D). however, the subtype of chorion and amnion were not reported by the authors: a male infant with HPE and otocephaly [13,14]; one twin with semilobar HPE and inv dup(15) marker chromosome and missense SHH gene mutation 1085 C 1 T (Ser 362 Leu) [14]. HPE and ectopia cordis were found in only one of diamniotic-dichorionic twin, however, whether the twin was monozygotic or dizygotic was not reported [15].…”