Antonio Novelli

Prevalence of recurrent pathogenic microdeletions and microduplications in over 9500 pregnancies.

The implementation of chromosomal microarray analysis (CMA) in prenatal testing for all patients has not achieved a consensus. Technical alternatives such as Prenatal BACs‐on‐BeadsTM (PNBoBsTM) have thus been applied. The aim of this study was to provide the frequencies of the submicroscopic defects detectable by PNBoBsTM under different prenatal indications.

Spectrum of epilepsy in terminal 1p36 deletion syndrome

Purpose: Previous reports have summarized the seizures types occurring in 1p36 deletion syndrome. To better define the spectrum of epilepsy, we studied 91 patients (median age 7.8 years) with confirmed 1p36 deletion.

Array-based comparative genomic hybridization in early-stage mycosis fungoides: recurrent deletion of tumor suppressor genes BCL7A, SMAC/DIABLO, and RHOF.

The etiology of mycosis fungoides (MF), the most frequent form of cutaneous T cell lymphoma (CTCL), is poorly understood. No specific genetic aberration has been detected, especially in early‐stage disease, possibly due to the clinical and histological heterogeneity of patient series and to the different sources of malignant cells (skin, blood, or lymph node) included in most studies. Frozen skin biopsies from 16 patients with early‐stage MF were studied using array‐based comparative genomic hybridization. A DNA pool from healthy donors was used as the reference. Results demonstrated recurrent loss of 19, 7p22.1‐p22.3, 7q11.1‐q11.23, 9q34.12, 12q24.31, and 16q22.3‐q23.1, and gain of 8q22.3‐q23.1 and 21q22.12. The 12q24.31 region was recurrently deleted in 7/16 patients. Real‐time PCR investigation for deletion of genes BCL7A, SMAC/DIABLO, and RHOF—three tumor suppressor genes with a putative role in hematological malignancies—demonstrated that they were deleted in 9, 10, and 13 cases, respectively. The identified genomic alterations and individual genes could yield important insights into the early steps of MF pathogenesis.

Syndromic craniosynostosis due to complex chromosome 5 rearrangement and MSX2 gene triplication

Craniosynostosis is a common birth defect (∼1/3,000 births) resulting from chromosome imbalances, gene mutations or unknown causes. We report a 6‐month‐old female with multiple sutural synostosis and prenatal onset growth deficiency, developmental delay, facial dysmorphism, congenital heart defect, and inguinal hernia. An integrated approach of standard cytogenetics, mBAND, locus‐specific FISH, and 75 kb resolution array‐CGH disclosed a complex chromosome 5 rearrangement, resulting in 3 paracentric inversions, 2 between‐arm insertions, and partial duplication of 5q35. An extra copy of the MSX2 gene, which maps within the duplicated segment and is mutated in Boston‐type craniosynostosis, was confirmed by molecular cytogenetic studies. Our study confirms that early fusion of cranial sutures commonly observed in the dup(5q) syndrome is caused by triplication of the MSX2 gene and strongly supports the crucial role of this gene in the development of craniofacial structures.

2q31.2q32.3 Deletion Syndrome : Report of an Adult Patient

A 36‐year‐old patient with a disorder characterized by severe mental retardation, behavioral problems, dysmorphic face, “muscular build,” and hand/foot anomalies, is reported. Following a diagnosis of de novo pericentric inversion of chromosome 8 based on standard cytogenetic analysis, a subsequent 75 kb array‐CGH investigation disclosed a deletion spanning for about 13.7 Mb in the 2q31.2q32.3 region. Whole painting of chromosome 8 established the intrachromosomal nature of the rearrangement and FISH analysis with locus‐specific probes confirmed the deletion on the long arm of chromosome 2. The deleted region, clinical outcome, and medical history in this patient are mainly superimposable to those reported in a published 8‐year‐old boy, suggesting that this genomic segment is prone to rearrangements and its hemizygosity gives rise to a clinically recognizable syndrome. The role of some genes mapping in the deleted region and related with distinct disorders is discussed. Interestingly, deletion of MSTN gene, a negative regulator of muscle growth, was associated in our patient with a “muscular build,” a feature which could be regarded as a handle for clinical recognition of this syndrome.

Nablus mask‐like facial syndrome is caused by a microdeletion of 8q detected by array‐based comparative genomic hybridization

In 2000, Teebi reported on a 4‐year‐old boy with a distinctive pattern of malformation, which he termed the “Nablus mask‐like facial syndrome” (OMIM# 608156). Characterization of this syndrome has been difficult because of the paucity of patients described in the medical literature and its unknown etiology and pathogenesis. We present two patients with Nablus mask‐like facial syndrome who both display a microdeletion in the 8q21‐8q22 region detected by array‐based comparative genomic hybridization. Patient 1, a boy, has a distinct facial appearance characterized by severe blepharophimosis, tight‐appearing glistening facial skin, sparse and unruly hair, a flat and broad nose, and distinctive ears that are triangular in shape with prominent antihelices. He also demonstrates camptodactyly, contractures, unusual dentition, cryptorchidism, mild developmental delay, and a happy demeanor. Patient 2, a girl with a strikingly similar phenotype, was previously described in a report by Salpietro et al. 2003 . She has distinctive ears, dental anomalies, and developmental delay. The etiology of her pattern of malformation was not identified at that time. Although high‐resolution chromosome and subtelomeric FISH analyses were normal, array‐based comparative genomic hybridization revealed an approximately 4 Mb deletion involving the 8q21.3‐8q22.1 region in both patients. This region encompasses a number of genes that may contribute to this unique phenotype. These results demonstrate a chromosomal microdeletion as the etiology of Nablus mask‐like facial syndrome and emphasize the diagnostic utility of array‐based comparative genomic hybridization in the evaluation of multiple malformation syndromes of previously unrecognized causation.

Further characterization of the new microdeletion syndrome of 16p11.2-p12.2.

Using aCGH, we have identified a pericentromeric deletion, spanning about 8.2 Mb, within 16p11.2–p12.2 in a patient with developmental delay (DD) and dysmorphic features. This deletion arose de novo and is flanked by segmental duplications. The proposita was the only child of healthy nonconsanguineous parents, born after an uneventful pregnancy, at 40 weeks gestation, by normal delivery. She was referred to us at age

Association of syndromic mental retardation with an Xq12q13.1 duplication encompassing the oligophrenin 1 gene

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Multiorgan autoimmunity in a Turner syndrome patient with partial monosomy 2q and trisomy 10p

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Geroderma osteodysplastica maps to a 4 Mb locus on chromosome 1q24.

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