Predicting fetoplacental chromosomal mosaicism during non-invasive prenatal testing.

OBJECTIVE: Non-invasive prenatal detection of aneuploidies can be achieved with high accuracy through sequencing of cell-free maternal plasma DNA in the maternal blood plasma. However, false positive and negative non-invasive prenatal testing (NIPT) results remain. Fetoplacental mosaicism is the main cause for false positive and false negative NIPT. We set out to develop a method to detect placental chromosomal mosaicism via genome-wide circulating cell-free maternal plasma DNA screening. METHOD: Aneuploidy detection was combined with fetal fraction determination to enable the detection of placental mosaicism. This pipeline was applied to whole genome sequencing data derived from 19 735 plasma samples. Following an abnormal NIPT, test results were validated by conventional invasive prenatal or postnatal genetic testing. RESULTS: Respectively 3.2% (5/154), 12.8% (5/39), and 13.3% (2/15) of trisomies 21, 18, and 13 were predicted and confirmed to be mosaic. The incidence of other, rare autosomal trisomies was ~0.3% (58/19,735), 45 of which were predicted to be mosaic. Twin pregnancies with discordant fetal genotypes were predicted and confirmed. CONCLUSION: This approach permits the non-invasive detection of fetal autosomal aneuploidies and identifies pregnancies with a high risk of fetoplacental mosaicism. Knowledge about the presence of chromosomal mosaicism in the placenta influences risk estimation, genetic counseling, and improves prenatal management.

Malignant hyperthermia in a 4-year-old girl during anesthesia induction with sevoflurane and succinylcholine for congenital ptosis surgery.

Malignant hyperthermia (MH) is a rare pharmacogenic disorder of skeletal muscle calcium regulation, resulting from general anesthesia that can be fatal. Most cases are caused by administration of volatile anesthetics or depolarizing muscle relaxants. It has been generally reported that both of sevoflurane and succinylcholine can induce the delayed onset of MH. Here, we report a case of malignant hyperthermia in a four-year-old girl during anesthesia induction for unilateral congenital ptosis surgery, two minutes after sevoflurane and succinylcholine administration. The crisis was atypical but early recognized and managed by administration of dantrolene with symptomatic treatment.

A Novel Missense Variant in the PVRL4 Gene Underlying Ectodermal Dysplasia-Syndactyly Syndrome in a Turkish Child.

Ectodermal dysplasia-syndactyly syndrome is a rare autosomal recessive congenital disorder caused by mutations in PVRL4 coding for nectin-4. Five different mutations in the PVRL4 gene, including 3 homozygous missense mutations, have been reported. Here, we present an unreported missense variant (c.247C>T, p.His83Tyr) in a consanguineous Turkish family.

SPG20 mutation in three siblings with familial hereditary spastic paraplegia.

Troyer syndrome (MIM#275900) is an autosomal recessive form of complicated hereditary spastic paraplegia. It is characterized by progressive lower extremity spasticity and weakness, dysarthria, distal amyotrophy, developmental delay, short stature, and subtle skeletal abnormalities. It is caused by deleterious mutations in the SPG20 gene, encoding spartin, on Chromosome 13q13. Until now, six unrelated families with a genetically confirmed diagnosis have been reported. Here we report the clinical findings in three brothers of a consanguineous Moroccan family, aged 24, 17, and 7 yr old, with spastic paraplegia, short stature, motor and cognitive delay, and severe intellectual disability. Targeted exon capture and sequencing showed a homozygous nonsense mutation in the SPG20 gene, c.1369C>T (p.Arg457*), in the three affected boys.

Bilateral renal tumors in an adult man with Smith-Magenis syndrome: The role of the FLCN gene.

Smith-Magenis syndrome (SMS) is a contiguous-gene disorder most commonly caused by a deletion of chromosome 17p11.2. We report a 57 year-old man with SMS who presents bilateral renal tumors. This is most likely related to haploinsufficiency of FLCN gene, located in the deleted region, and a known tumor suppressor gene. Haploinsufficiency of FLCN causes Birt-Hogg-Dubé syndrome (BHDS), characterized by pulmonary cysts, renal and skin tumors. The present observation suggests that the follow-up of patients with SMS should also focus on possible manifestations of BHDS.