Mandibular dysostosis without microphthalmia caused by OTX2 deletion.

Mutations in OTX2 are mostly identified in patients with anophthalmia/microphthalmia with variable severity. The OTX2 homeobox gene plays a crucial role in craniofacial morphogenesis during early embryo development. We report for the first time a patient with a mandibular dysostosis caused by a 120 kb deletion including the entire coding sequence of OTX2, identified by array CGH. No ocular malformations were identified after extended ophthalmologic examination. Our data refine the clinical spectrum associated with OTX2 mutations and suggests that OTX2 haploinsufficiency should be considered as a possible cause for isolated mandibular dysostosis. © 2016 Wiley Periodicals, Inc.

Disruption of the SEMA3D gene in a patient with congenital heart defects.

Congenital heart defect (CHD) is the leading malformation among newborns. However, its genetic basis remains mostly unknown. We report a child with transposition of the great arteries, ventricular septal defect, and coarctation of the aorta. By array comparative genomic hybridization, we identified a duplication of the 5' half of semaphorin3D (SEMA3D). Breakpoint sequencing and fiber fluorescent in situ hybridization showed tandem duplication. Expression studies showed a higher level of SEMA3D mRNA in patient's lymphoblasts versus controls. Moreover, we demonstrated the presence of a truncated SEMA3D poly-A tailed mRNA, resulting from an abnormal transcription of SEMA3D partial duplication. Sema3D is an axon guidance protein essential for the correct migration of cardiac neural crest cells (CNCC) into the outflow tract. Sema3D(-/-) mice present with CHD but its role in humans remains unclear. Our results suggest that truncated SEMA3D may have hampered the migration of CNCC during heart development, contributing to patient's CHD.

Fryns type mesomelic dysplasia of the upper limbs caused by inverted duplications of the HOXD gene cluster.

The HoxD cluster is critical for vertebrate limb development. Enhancers located in both the telomeric and centromeric gene deserts flanking the cluster regulate the transcription of HoxD genes. In rare patients, duplications, balanced translocations or inversions misregulating HOXD genes are responsible for mesomelic dysplasia of the upper and lower limbs. By aCGH, whole-genome mate-pair sequencing, long-range PCR and fiber fluorescent in situ hybridization, we studied patients from two families displaying mesomelic dysplasia limited to the upper limbs. We identified microduplications including the HOXD cluster and showed that microduplications were in an inverted orientation and inserted between the HOXD cluster and the telomeric enhancers. Our results highlight the existence of an autosomal dominant condition consisting of isolated ulnar dysplasia caused by microduplications inserted between the HOXD cluster and the telomeric enhancers. The duplications likely disconnect the HOXD9 to HOXD11 genes from their regulatory sequences. This presumptive loss-of-function may have contributed to the phenotype. In both cases, however, these rearrangements brought HOXD13 closer to telomeric enhancers, suggesting that the alterations derive from the dominant-negative effect of this digit-specific protein when ectopically expressed during the early development of forearms, through the disruption of topologically associating domain structure at the HOXD locus.

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.

Wilms' tumor in patients with 9q22.3 microdeletion syndrome suggests a role for PTCH1 in nephroblastomas.

Nephroblastoma (Wilms' tumor; WT) is the most common renal tumor of childhood. To date, several genetic abnormalities predisposing to WT have been identified in rare overgrowth syndromes. Among them, abnormal methylation of the 11p15 region, GPC3 and DIS3L2 mutations, which are responsible for Beckwith-Wiedemann, Simpson-Golabi-Behmel and Perlman syndromes, respectively. However, the underlying cause of WT remains unknown in the majority of cases. We report three unrelated patients who presented with WT in addition to a constitutional 9q22.3 microdeletion and dysmorphic/overgrowth syndrome. The size of the deletions was variable (ie, from 1.7 to 8.9 Mb) but invariably encompassed the PTCH1 gene. Subsequently, we identified a somatic PTCH1 nonsense mutation in the renal tumor of one patient. In addition, by array comparative genomic hybridization method, we analyzed the DNA extracted from the blood samples of nine patients with overgrowth syndrome and WT, but did not identify any deleterious chromosomal imbalances in these patients. These findings strongly suggest that patients with constitutional 9q22.3 microdeletion have an increased risk of WT, and that PTCH1 have a role in the pathogenesis of nephroblastomas.