A Case of CDKL5 Deficiency Due to an X Chromosome Pericentric Inversion: Delineation of Structural Rearrangements as an Overlooked Recurrent Pathological Mechanism.

CDKL5 deficiency disorder (CDD) is an X-linked dominant epileptic encephalopathy, characterized by early-onset and drug-resistant seizures, psychomotor delay, and slight facial features. Genomic variants inactivating or impairing its protein product kinase activity have been reported, making next-generation sequencing (NGS) and chromosomal microarray analysis (CMA) the standard diagnostic tests. We report a suspicious case of CDD in a female child who tested negative upon NGS and CMA and harbored an X chromosome de novo pericentric inversion.

Structural rearrangements as a recurrent pathogenic mechanism for SETBP1 haploinsufficiency.

Chromosomal structural rearrangements consist of anomalies in genomic architecture that may or may not be associated with genetic material gain and loss. Evaluating the precise breakpoint is crucial from a diagnostic point of view, highlighting possible gene disruption and addressing to appropriate genotype-phenotype association. Structural rearrangements can either occur randomly within the genome or present with a recurrence, mainly due to peculiar genomic features of the surrounding regions.

Case report: A new 6q21q22.1 interstitial deletion case in a girl with cerebellar vermis hypoplasia and developmental delay and literature review.

Interstitial deletions involving 6q chromosomal region are rare. Less than 30 patients have been described to date, and fewer have been characterized by high-resolution techniques, such as chromosomal microarray. Deletions involving 6q21q22.

A novel case of 16q22.3 duplication syndrome in a child with overgrowth: case report and literature review.

Background: Distal chromosome 16 duplication syndrome (also known as 16q partial trisomy) is a very rare genetic disorder recently described in few clinical reports. 16q trisomy is generally associated with a multisystemic phenotype including intrauterine growth restriction (IUGR), brain and cardiac defects, intellectual disability (ID) and an increased risk of both prenatal and postnatal lethality. Smaller copy number variants (CNV) within the 16q region create partial trisomies, which occur less frequently than full trisomy 16q.

Intragenic inversions in NF1 gene as pathogenic mechanism in neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1), an autosomal dominant disorder characterized by skin pigmentary lesions and multiple cutaneous neurofibromas, is caused by neurofibromin 1 (NF1) loss of function variants. Currently, a molecular diagnosis is frequently established using a multistep protocol based on cDNA and gDNA sequence analysis and/or Multiplex Ligation-dependent Probe Amplification (MLPA) assay on genomic DNA, providing an overall detection rate of about 95-97%. The small proportion of clinically diagnosed patients, which at present do not obtain a molecular confirmation likely are mosaic, as their pathogenic variant may remain undetected due to low sensitivity of low coverage NGS approaches, or they may carry a type of pathogenic variant refractory to currently used technologies.

Neurological and Neuroimaging Features of -Related Recessive Hereditary Methemoglobinemia Type II.

Recessive hereditary methemoglobinemia (RHM) due to NADH-cytochrome b5 reductase deficiency is a rare disease caused by pathogenic variants in . Unlike type I, in RHM type II (RHM2), the enzymatic defect affects erythrocytes and all body tissues, thus resulting in cyanosis and neurological impairment. Although the first description of RHM2 dates back to the mid-1950s, detailed clinical and neuroimaging information are available for only a few patients.

Prevalence of copy number variants (CNVs) and rhGH treatment efficacy in an Italian cohort of children born small for gestational age (SGA) with persistent short stature associated with a complex clinical phenotype.

Purpose: Multiple factors influence intrauterine growth and lead to low birth sizes. The impact of genetic alterations on both pre- and post-natal growth is still largely unknown. The aim of this study was to investigate the prevalence of CNVs in an Italian cohort of SGA children with persistent short stature and complex clinical phenotype.

Clinical Application of Easychip 8x15K Platform in 4106 Pregnancies Without Ultrasound Anomalies.

Clinical utility of Array-CGH Easychip 8x15K platform can be assessed by testing its ability to detect the occurrence of pathogenic copy number variants (CNVs), and occurrence of variants of uncertain significance (VoUS) in pregnancies without structural fetal malformations. The demand of chromosomal microarray analysis in prenatal diagnosis is progressively increasing in uneventful pregnancies. However, depending on such platform resolution, a genome-wide approach also provides a high risk of detecting VoUS and incidental finding (IF) also defined as "toxic findings.

Schilbach-Rott syndrome associated with 9q22.32q22.33 duplication, involving the PTCH1 gene.

Schilbach-Rott syndrome (SRS, OMIM%164220) is a disorder of unknown aetiology that is characterised by hypotelorism, epichantal folds, cleft palate, dysmorphic face, hypospadia in males and mild mental retardation in some patients. To date, 5 families and 17 patients have exhibited this phenotype, and recurrence in two of these families suggests an autosomal dominant inheritance. SRS overlaps with a mild form of holoprosencephaly (HPE), but array-CGH analysis and sequencing of some HPE-related genes (SEPT9, SHH and TWIST) did not reveal any variants in at least one family.

Report of a Novel Missense Variant in a Boy With Short Stature and His Mother With Leri-Weill Dyschondrosteosis.

Heterozygous mutations in the gene or in the upstream and downstream enhancer elements are associated with 2-22% of cases of idiopathic short stature (OMIM #300582) and with 60% of cases of Leri-Weill dyschondrosteosis (OMIM #127300) with which female subjects are generally more severely affected. Approximately 80-90% of pathogenic variants are deletions or duplications, and the remaining 10-20% are point mutations that primarily give rise to missense variants. The clinical interpretation of novel variants, particularly missense variants, can be challenging and can remain of uncertain significance.

Juvenile Moyamoya and Craniosynostosis in a Child with Deletion 1p32p31: Expanding the Clinical Spectrum of 1p32p31 Deletion Syndrome and a Review of the Literature.

Moyamoya angiopathy (MA) is a rare cerebrovascular disorder characterised by the progressive occlusion of the internal carotid artery. Its aetiology is uncertain, but a genetic background seems likely, given the high MA familial rate. To investigate the aetiology of craniosynostosis and juvenile moyamoya in a 14-year-old male patient, we performed an array-comparative genomic hybridisation revealing a de novo interstitial deletion of 8.