Preimplantation genetic testing in patients with genetic susceptibility to cancer.

Data on preimplantation genetic testing (PGT-M) in patients with genetic susceptibility to cancer are scarce in the literature, while there is, in our experience, a growing familiarity with assisted reproduction techniques (ART) among pathogenic variant heterozygotes. We performed a retrospective multicenter study of PGT-M outcomes among French patients with genetic susceptibility to cancer. Our objectives were to collect data on this complex issue, and to help cancer geneticists counsel their patients of reproductive age. We also wanted to increase awareness regarding PGT-M among cancer genetics professionals. Patients from three university hospital cancer genetics clinics who had requested PGT-M between 2000 and 2019 were included retrospectively. Data were extracted from medical records. Patients were then contacted directly to collect missing and up-to-date information. Out of 41 eligible patients, 28 agreed explicitly to participate when contacted and were therefore included. They carried PV in VHL (n = 9), APC (n = 8), CDH1 (n = 5), STK11 (n = 2), AXIN2, BRCA1, MEN1, and FH (n = 1). Seven patients were denied PGT-M based on multidisciplinary team meetings or subsequently by the ART hospital teams, two changed their minds, and two were yet to start the process. PGT-M was successful in seven patients (25%), with a mean age at PGT-M request of 27. Most had von Hippel-Lindau. PGT-M failed in the remaining ten, with a mean age at PGT-M request of 32. The main reason for failure was non-implantation of the embryo. Of these, four patients were pursuing PGT-M at the time of last contact. PGT-M outcomes in patients with cancer susceptibility syndromes were satisfactory. These patients should be informed about PGT-M more systematically, which would imply greater awareness among cancer genetics professionals regarding ART. Our series was not representative of cancer susceptibility syndromes in general; the predominance of cases with syndromes characterized by early-onset, highly penetrant disease is explained by the restrictive French guidelines.

Molecular characterization of 1q44 microdeletion in 11 patients reveals three candidate genes for intellectual disability and seizures.

Patients with a submicroscopic deletion at 1q43q44 present with intellectual disability (ID), microcephaly, craniofacial anomalies, seizures, limb anomalies, and corpus callosum abnormalities. However, the precise relationship between most of deleted genes and the clinical features in these patients still remains unclear. We studied 11 unrelated patients with 1q44 microdeletion. We showed that the deletions occurred de novo in all patients for whom both parents' DNA was available (10/11). All patients presented with moderate to severe ID, seizures and non-specific craniofacial anomalies. By oligoarray-based comparative genomic hybridization (aCGH) covering the 1q44 region at a high resolution, we obtained a critical deleted region containing two coding genes-HNRNPU and FAM36A-and one non-coding gene-NCRNA00201. All three genes were expressed in different normal human tissues, including in human brain, with highest expression levels in the cerebellum. Mutational screening of the HNRNPU and FAM36A genes in 191 patients with unexplained isolated ID did not reveal any deleterious mutations while the NCRNA00201 non-coding gene was not analyzed. Nine of the 11 patients did not present with microcephaly or corpus callosum abnormalities and carried a small deletion containing HNRNPU, FAM36A, and NCRNA00201 but not AKT3 and ZNF238, two centromeric genes. These results suggest that HNRNPU, FAM36A, and NCRNA00201 are not major genes for microcephaly and corpus callosum abnormalities but are good candidates for ID and seizures.

Serpentine fibula-polycystic kidney syndrome caused by truncating mutations in NOTCH2.

Serpentine fibula-polycystic kidney syndrome (SFPKS) is a rare disorder characterized by the association of craniofacial anomalies, radiological findings (wormian bones, elongated and bowed fibulae), polycystic kidneys, and normal intelligence. SFPKS shares many similarities with Hajdu-Cheney syndrome (HCS). We and others recently showed that truncating mutations in the last exon of NOTCH2 cause HCS. Here, we identify by Sanger sequencing two different heterozygous truncating mutations in the last exon of NOTCH2 in two unrelated patients with SFPKS. In one family, we show that the mutation occurred de novo. These findings demonstrate that SFPKS and HCS are both conditions caused by NOTCH2 mutations.

Genotype-Phenotype Relationship in Patients and Relatives with SHOX Region Anomalies in the French Population.

BACKGROUND: The aim of our study was to describe a large population with anomalies involving the SHOX region, responsible for idiopathic short stature and Léri-Weill dyschondrosteosis (LWD), and to identify a possible genotype/phenotype correlation. METHODS: We performed a retrospective multicenter study on French subjects with a SHOX region anomaly diagnosed by multiplex ligation-dependent probe amplification or Sanger sequencing. Phenotypes were collected in each of the 7 genetic laboratories practicing this technique for SHOX analysis. RESULTS: Among 205 index cases and 100 related cases, 91.3% had LWD. For index cases, median age at evaluation was 11.7 (9.0; 15.9) years and mean height standard deviation score was -2.3 ± 1.1. A deletion of either SHOX or PAR1 or both was found in 74% of patients. Duplications and point mutations/indels affected 8 and 18% of the population, respectively. Genotype-phenotype correlation showed that deletions were more frequently associated with Madelung deformity and mesomelic shortening in girls, as well as with presence of radiologic anomalies, than duplications. CONCLUSIONS: Our results highlight genotype-phenotype relationships in the French population with a SHOX defect and provide new information showing that clinical expression is milder in cases of duplication compared to deletions.

Autosomal insertional translocation mimicking an X-linked mode of inheritance.

Unbalanced insertional translocations are a rare cause of intellectual disability. An unbalanced insertional translocation is a rare chromosomal imbalance, which may result from a balanced insertional translocation present in a phenotypically normal parent. We report here three brothers with intellectual disability, short stature, microcephaly, craniofacial anomalies and small testes. Since their parents and their sister were all phenotypically normal, the pattern of the family suggested an X-linked mode of inheritance. Surprisingly, we identified by array comparative genomic hybridization (aCGH) and fluorescent in situ hybridization (FISH) in the three brothers an 8q22.3q23.2 deletion resulting from a balanced insertional translocation present in their healthy father. The deletion encompassed the ZFPM2 gene known to be involved in gonadal development, which is consistent with the small testes and abnormal endocrine dosages in the affected brothers. The present report also illustrates that parental analyses by aCGH or qPCR methods are not sufficient when a de novo deletion or duplication is identified in an affected child and that FISH analysis should be performed on metaphase spreads in both parents to deliver an accurate genetic counseling.