A Novel KIDINS220 Pathogenic Variant Associated with the Syndromic Spastic Paraplegia SINO: An Expansion of the Brain Malformation Spectrum and a Literature Review.

Background/objectives: Identifying novel variants in very rare disease genes can be challenging when patients exhibit a complex phenotype that expands the one described, and we provide such an example here. A few terminal truncating variants in cause spastic paraplegia (SP), intellectual disability (ID), nystagmus, and obesity (SINO, MIM #617296). Prompted by the result of next-generation sequencing on a patient referred for SP associated with complex brain dysmorphisms, we reviewed the phenotype of SINO patients focusing on their brain malformations, mainly described in prenatal age and first years of life, and tried to understand if the predicted effect of the mutant kidins220 may have caused them.

Low-grade parental gonosomal mosaicism in CHD2 siblings with Smith-Magenis-like syndrome.

Loss-of-function CHD2 (chromodomain helicase DNA-binding protein 2) mutations are associated with a spectrum of neurodevelopmental disorders often including early-onset generalized seizures, photosensitivity, and epileptic encephalopathies. Patients show psychomotor delay/intellectual disability (ID), autistic features, and behavior disorders, such as aggression and impulsivity. Most reported cases are sporadic with description of germline mosaicism only in two families.

From clinical findings to the pathomechanism of poikiloderma with neutropenia.

The clinical problem of a non-healing fistula in ano in a child affected with poikiloderma with neutropenia (PN) was the stimulus for an innovative study by Parajuli et al. that sheds light on the pathological mechanisms in this disease. Multiparametric analyses of the patient's blood mononuclear cells by cell culture, flow cytometry and multiplex cytokine assay suggested a block of monocyte differentiation.

Case report: atypical Silver-Russell syndrome patient with hand dystonia: the valuable support of the consensus statement to the wide syndromic spectrum.

The amount of Insulin Growth Factor 2 (IGF2) controls the rate of embryonal and postnatal growth. The and adjacent are the imprinted genes of the telomeric cluster in the 11p15 chromosomal region regulated by differentially methylated regions (DMRs) or imprinting centers (ICs): H19/IGF2:IG-DMR (IC1). Dysregulation due to IC1 Loss-of-Methylation (LoM) or Gain-of-Methyaltion (GoM) causes Silver-Russell syndrome (SRS) or Beckwith-Wiedemann syndrome (BWS) disorders associated with growth retardation or overgrowth, respectively.

Rare Diseases: Implementation of Molecular Diagnosis, Pathogenesis Insights and Precision Medicine Treatment.

Rare Diseases (RD) do not have an exact definition since local authorities define the criteria in different ways, from fewer than 5 people in 10,000, according to the European Union, to the standard world average of 40 cases per 100,000 people [...

Modeling RTT Syndrome by iPSC-Derived Neurons from Male and Female Patients with Heterogeneously Severe Hot-Spot MECP2 Variants.

Rett syndrome caused by variants is characterized by a heterogenous clinical spectrum accounted for in 60% of cases by hot-spot variants. Focusing on the most frequent variants, we generated in vitro iPSC-neurons from the blood of RTT girls with p.Arg133Cys and p.

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 .

12q21 Interstitial Deletions: Seven New Syndromic Cases Detected by Array-CGH and Review of the Literature.

Interstitial deletions of the long arm of chromosome 12 are rare, with a dozen patients carrying a deletion in 12q21 being reported. Recently a critical region (CR) has been delimited and could be responsible for the more commonly described clinical features, such as developmental delay/intellectual disability, congenital genitourinary and brain malformations. Other, less frequent, clinical signs do not seem to be correlated to the proposed CR.

Germline variants in genes of the subcortical maternal complex and Multilocus Imprinting Disturbance are associated with miscarriage/infertility or Beckwith-Wiedemann progeny.

Beckwith-Wiedemann syndrome (BWS, OMIM # 130650) is an imprinting disorder, associated with overgrowth and increased risk of embryonal tumors. Patients carrying hypomethylation in the KCNQ1OT1:TSS DMR (11p15.5) show MLID (Multilocus Imprinting Disturbance) upon epimutations at other imprinted regions.

Targeted whole exome sequencing and Drosophila modelling to unveil the molecular basis of primary ovarian insufficiency.

Study Question: Can a targeted whole exome sequencing (WES) on a cohort of women showing a primary ovarian insufficiency (POI) phenotype at a young age, combined with a study of copy number variations, identify variants in candidate genes confirming their deleterious effect on ovarian function?

Summary Answer: This integrated approach has proved effective in identifying novel candidate genes unveiling mechanisms involved in POI pathogenesis.

What Is Known Already: POI, a condition occurring in 1% of women under 40 years of age, affects women's fertility leading to a premature loss of ovarian reserve. The genetic causes of POI are highly heterogeneous and several determinants contributing to its prominent oligogenic inheritance pattern still need to be elucidated.

Spontaneous chromosomal instability in peripheral blood lymphocytes from two molecularly confirmed Italian patients with Hereditary Fibrosis Poikiloderma: insights into cancer predisposition.

Two Italian patients with the initial clinical diagnosis of Rothmund-Thomson syndrome were negative for RECQL4 mutations but showed in peripheral blood cells a spontaneous chromosomal instability significantly higher than controls. Revisiting after time their clinical phenotype, the suggestive matching with the autosomal dominant syndrome Poikiloderma, Hereditary Fibrosing with Tendon Contracture, Myopathy and Pulmonary fibrosis (POIKTMP) was confirmed by identification of the c.1879A>G (p.

Genes for RNA-binding proteins involved in neural-specific functions and diseases are downregulated in Rubinstein-Taybi iNeurons.

Taking advantage of the fast-growing knowledge of RNA-binding proteins (RBPs) we review the signature of downregulated genes for RBPs in the transcriptome of induced pluripotent stem cell neurons (iNeurons) modelling the neurodevelopmental Rubinstein Taybi Syndrome (RSTS) caused by mutations in the genes encoding CBP/p300 acetyltransferases. We discuss top and functionally connected downregulated genes sorted to "RNA processing" and "Ribonucleoprotein complex biogenesis" Gene Ontology clusters. The first set of downregulated RBPs includes members of hnRNHP (A1, A2B1, D, G, H2-H1, MAGOHB, PAPBC), core subunits of U small nuclear ribonucleoproteins and Serine-Arginine splicing regulators families, acting in precursor messenger RNA alternative splicing and processing.

Histone Deacetylase Inhibitors Ameliorate Morphological Defects and Hypoexcitability of iPSC-Neurons from Rubinstein-Taybi Patients.

Rubinstein-Taybi syndrome (RSTS) is a rare neurodevelopmental disorder caused by mutations in or genes encoding CBP/p300 lysine acetyltransferases. We investigated the efficacy of the histone deacetylase inhibitor (HDACi) Trichostatin A (TSA) in ameliorating morphological abnormalities of iPSC-derived young neurons from P149 and P34 -mutated patients and hypoexcitability of mature neurons from P149. Neural progenitors from both patients' iPSC lines were cultured one week with TSA 20 nM and, only P149, for 6 weeks with TSA 0.

8p23.2-pter Microdeletions: Seven New Cases Narrowing the Candidate Region and Review of the Literature.

To date only five patients with 8p23.2-pter microdeletions manifesting a mild-to-moderate cognitive impairment and/or developmental delay, dysmorphisms and neurobehavioral issues were reported. The smallest microdeletion described by Wu in 2010 suggested a critical region (CR) of 2.

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.