Loss-of-function in RBBP5 results in a syndromic neurodevelopmental disorder associated with microcephaly.

Purpose: Epigenetic dysregulation has been associated with many inherited disorders. RBBP5 (HGNC:9888) encodes a core member of the protein complex that methylates histone 3 lysine-4 and has not been implicated in human disease.

Methods: We identify 5 unrelated individuals with de novo heterozygous variants in RBBP5.

SMC1A epilepsy syndrome: clinical data from a large international cohort.

SMC1A epilepsy syndrome or developmental and epileptic encephalopathy-85 with or without midline brain defects (DEE85, OMIM #301044) is an X-linked neurologic disorder associated with mutations of the SMC1A gene, which is also responsible for about 5% of patients affected by Cornelia de Lange syndrome spectrum (CdLS). Only described in female patients, SMC1A epilepsy syndrome is characterized by the onset of severe refractory epileptic seizures in the first year of life, global developmental delay, a variable degree of intellectual disability, and dysmorphic facial features not typical of CdLS. This was a descriptive observational study for the largest international cohort with this specific disorder.

Comparison of first-tier whole-exome sequencing with a multi-step traditional approach for diagnosing paediatric outpatients: An Italian prospective study.

Background: The recent guidelines suggest the use of genome-wide analyses, such as whole exome sequencing (WES), at the beginning of the diagnostic approach for cases with suspected genetic conditions. However, in many realities it still provides for the execution of a multi-step pathway, thus requiring several genetic tests to end the so-called 'diagnostic odyssey'.

Methods: We reported the results of GENE Project (Genomic analysis Evaluation NEtwork): a multicentre prospective cohort study on 125 paediatric outpatients with a suspected genetic disease in which we performed first-tier trio-WES, including exome-based copy number variation analysis, in parallel to a 'traditional approach' of two/three sequential genetic tests.

Application of the Face2Gene tool in an Italian dysmorphological pediatric clinic: Retrospective validation and future perspectives.

Neurodevelopmental disorders exhibit recurrent facial features that can suggest the genetic diagnosis at a glance, but recognizing subtle dysmorphisms is a specialized skill that requires very long training. Face2Gene (FDNA Inc) is an innovative computer-aided phenotyping tool that analyses patient's portraits and suggests 30 candidate syndromes with similar morphology in a prioritized list. We hypothesized that the software could support even expert physicians in the diagnostic workup of genetic conditions.

FOXI3 pathogenic variants cause one form of craniofacial microsomia.

Craniofacial microsomia (CFM; also known as Goldenhar syndrome), is a craniofacial developmental disorder of variable expressivity and severity with a recognizable set of abnormalities. These birth defects are associated with structures derived from the first and second pharyngeal arches, can occur unilaterally and include ear dysplasia, microtia, preauricular tags and pits, facial asymmetry and other malformations. The inheritance pattern is controversial, and the molecular etiology of this syndrome is largely unknown.

Patients with DeSanto-Shinawi syndrome: Further extension of phenotype from Italy.

Here we describe three patients with neurodevelopmental disorders characterized by mild-to-moderate intellectual disability, mildly dysmorphic features, and hirsutism, all of which carry de novo sequence variants in the WW domain-containing adaptor of the coiled-coil (WAC) gene; two of these-c.167delA, p.(Asn56I1efs*136) and c.

Expanding the Molecular Spectrum of Gene Defects in 33 Patients with a Clinical Presentation of KBG Syndrome.

KBG syndrome (KBGS) is a neurodevelopmental disorder caused by the Ankyrin Repeat Domain 11 () haploinsufficiency. Here, we report the molecular investigations performed on a cohort of 33 individuals with KBGS clinical suspicion. By using a multi-testing genomic approach, including gene sequencing, Chromosome Microarray Analysis (CMA), and RT-qPCR gene expression assay, we searched for pathogenic alterations in .

A missense mutation in DDRGK1 gene associated to Shohat-type spondyloepimetaphyseal dysplasia: Two case reports and a review of literature.

Spondylo-epi-metaphyseal dysplasia Shohat type (SEMDSH, OMIM # 602557) is a rare skeletal dysplasia. Until recently, only eight patients of five families have been reported. The disorder is characterized by severely disproportionate short stature with a short neck, small trunk with abdominal distension, and short lower limbs.

Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome.

Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture and/or function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates including CYCLIN E1/2 and NOTCH for degradation via the ubiquitin proteasome system. We used a genotype-first approach and global data-sharing platforms to identify 35 individuals harboring de novo and inherited FBXW7 germline monoallelic chromosomal deletions and nonsense, frameshift, splice-site, and missense variants associated with a neurodevelopmental syndrome.

Cantù syndrome: Report of a patient with a novel variant in KCNJ8 and revision of literature.

Cantù syndrome (CS) is a rare multisystemic disorder, characterized by congenital hypertrichosis, macrocephaly, facial dysmorphisms, cardiomegaly, vascular, and skeletal anomalies. From the cognitive point of view, most of the patients show a mild speech delay and a few of them present intellectual disability and learning difficulties. To date, most CS-reported cases are caused by heterozygous ABCC9 gene mutations.

Neuropsychiatric Functioning in CDLS: A Detailed Phenotype and Genotype Correlation.

Behavioural phenotype and autism-related traits of 38 patients affected by Cornelia de Lange syndrome (CdLS) were assessed using a specific neuropsychiatric protocol. Subsequently,we search for possible genotype-phenotype correlations comparing individuals with NIPBL variants and patients with negative molecular results. Firstly results showed a higher percentage of subjects with normal intellectual quotient (IQ) and borderline IQ; adaptive skills were lower than expected for age in all participants.

Cornelia de Lange Syndrome: From a Disease to a Broader Spectrum.

Cornelia de Lange syndrome (CdLS) is a genetic disease that exemplifies the evolution of knowledge in the field of rare genetic disorders. Originally described as a unique pattern of major and minor anomalies, over time this syndrome has been shown to be characterized by a significant variability of clinical expression. By increasing the number of patients described, knowledge of the natural history of the condition has been enriched with the demonstration of the relative frequency of various potential comorbidities.

ANKRD11 variants: KBG syndrome and beyond.

Mutations affecting the transcriptional regulator Ankyrin Repeat Domain 11 (ANKRD11) are mainly associated with the multisystem developmental disorder known as KBG syndrome, but have also been identified in individuals with Cornelia de Lange syndrome (CdLS) and other developmental disorders caused by variants affecting different chromatin regulators. The extensive functional overlap of these proteins results in shared phenotypical features, which complicate the assessment of the clinical diagnosis. Additionally, re-evaluation of individuals at a later age occasionally reveals that the initial phenotype has evolved toward clinical features more reminiscent of a developmental disorder different from the one that was initially diagnosed.

Maternal Uniparental Disomy of Chromosome 20 (UPD(20)mat) as Differential Diagnosis of Silver Russell Syndrome: Identification of Three New Cases.

Silver Russell Syndrome (SRS, MIM #180860) is a rare growth retardation disorder in which clinical diagnosis is based on six features: pre- and postnatal growth failure, relative macrocephaly, prominent forehead, body asymmetry, and feeding difficulties (Netchine-Harbison clinical scoring system (NH-CSS)). The molecular mechanisms consist in (epi)genetic deregulations at multiple loci: the loss of methylation (LOM) at the paternal :IG-DMR (chr11p15.5) (50%) and the maternal uniparental disomy of chromosome 7 (UPD(7)mat) (10%) are the most frequent causes.

Burden of care in families of patients with rare genetic diseases: analysis of a large Italian cohort.

In the last decade, the number of children and youth with special health care needs (CYSHCN) is increased as a result of the improvement of neonatal and pediatric assistance. The aim of our study was to describe the burden of care of the families caring a CYSHCN in our country, evaluating their living condition in order to explore socio-economic characteristics, health problems, needs and their adaptation processes trying to reach a balance between the needs of the disabled child and those of the other family members. We administered a questionnaire to the parents of CYSHCN during a routine clinical evaluation.

Lithium as a possible therapeutic strategy for Cornelia de Lange syndrome.

Cornelia de Lange Syndrome (CdLS) is a rare developmental disorder affecting a multitude of organs including the central nervous system, inducing a variable neurodevelopmental delay. CdLS malformations derive from the deregulation of developmental pathways, inclusive of the canonical WNT pathway. We have evaluated MRI anomalies and behavioral and neurological clinical manifestations in CdLS patients.

Complex nutritional deficiencies in a large cohort of Italian patients with Cornelia de Lange syndrome spectrum.

Cornelia de Lange syndrome Spectrum (CdLSp) is characterized by intellectual disability, facial dysmorphisms, and growth impairment. Although eating difficulties are a well-known feature of the disease, there is no data regarding the nutritional deficiencies of these patients. The food intake was tracked using a dietary transcription provided by the family/caregivers, biochemical nutritional parameters were measured with laboratory tests and through an accurate clinical evaluation of the incidence of qualitative and quantitative imbalances in a cohort of 73 patients with CdLSp ware determined.

Williams-Beuren Syndrome and celiac disease: A real association?

Celiac disease (CD) screening in patients with Williams-Beuren Syndrome (WBS) is suggested, although data described in literature are discordant regarding CD prevalence in WBS. We retrospectively collected data from 101 WBS Italian patients [mean age: 13.5 years], to clarify the CD prevalence in a large cohort.

Nissen fundoplication in Cornelia de Lange syndrome spectrum: Who are the potential candidates?

Cornelia de Lange spectrum (CdLSp) is a rare genetic condition characterized by intellectual disability, facial dysmorphisms, major malformations, growth impairment, and development delay. Approximately 80% of CdLSp patients have gastroesophageal reflux disease (GERD) with a varied clinical presentation. The aim of this study is to define potential clinical/genetic risk factors based on the clinical phenotype description of CdLSp patients with severe GERD who underwent surgical treatment.

De novo heterozygous missense and loss-of-function variants in CDC42BPB are associated with a neurodevelopmental phenotype.

CDC42BPB encodes MRCKβ (myotonic dystrophy-related Cdc42-binding kinase beta), a serine/threonine protein kinase, and a downstream effector of CDC42, which has recently been associated with Takenouchi-Kosaki syndrome, an autosomal dominant neurodevelopmental disorder. We identified 12 heterozygous predicted deleterious variants in CDC42BPB (9 missense, 2 frameshift, and 1 nonsense) in 14 unrelated individuals (confirmed de novo in 11/14) with neurodevelopmental disorders including developmental delay/intellectual disability, autism, hypotonia, and structural brain abnormalities including cerebellar vermis hypoplasia and agenesis/hypoplasia of the corpus callosum. The frameshift and nonsense variants in CDC42BPB are expected to be gene-disrupting and lead to haploinsufficiency via nonsense-mediated decay.

Chromatinopathies: A focus on Cornelia de Lange syndrome.

In recent years, many genes have been associated with chromatinopathies classified as "Cornelia de Lange Syndrome-like." It is known that the phenotype of these patients becomes less recognizable, overlapping to features characteristic of other syndromes caused by genetic variants affecting different regulators of chromatin structure and function. Therefore, Cornelia de Lange syndrome diagnosis might be arduous due to the seldom discordance between unexpected molecular diagnosis and clinical evaluation.

13q mosaic deletion including associated to mild phenotype and no cancer outcome - case report and review of the literature.

Background: The 13q deletion syndrome is a rare chromosome disorder associated with wide phenotypic spectrum, which is related to size and location of the deleted region and includes intellectual disability, growth retardation, craniofacial dysmorphisms, congenital malformations, and increased risk of retinoblastoma.

Case Presentation: Here, we report on a teenage boy with a mild phenotype characterized by obesity, hyperactivity, dysphagia, dysgraphia, sleep disturbance, and minor dysmorphic features (round face, bushy eyebrows, and stubby hands). Array Comparative Genomic Hybridization on blood identified a mosaic 13q14.

Use of nutritional devices in Cornelia de Lange syndrome: Data from a large Italian cohort.

Cornelia de Lange syndrome (CdLS) is a genetic condition characterized by intellectual disability, peculiar facial dysmorphisms, multiorgan malformations, and growth problems. Majority cases of CdLS are caused by mutations in genes of Cohesin pathway. Although feeding problems are a well-known feature, no specific data have been published about the use of nutritional devices.

Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement.

Cornelia de Lange syndrome (CdLS) is an archetypical genetic syndrome that is characterized by intellectual disability, well-defined facial features, upper limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in any one of seven genes, all of which have a structural or regulatory function in the cohesin complex. Although recent advances in next-generation sequencing have improved molecular diagnostics, marked heterogeneity exists in clinical and molecular diagnostic approaches and care practices worldwide.