Intestinal pseudo-obstruction in a patient with Kleefstra syndrome

Aim: To present a case of intestinal pseudo-obstruction in a paediatric patient with Kleefstra syndrome type 1 as a new clinical feature of this rare genetic disorder. Case report: A seven-year-old patient was admitted to the emergency department for nausea and vomiting. Clinical examination showed distended, meteoristic abdomen without detectable peristaltic sound. Abdominal X-ray revealed air-fluid levels and possible right subdiaphragmatic air collection. An urgent exploratory laparotomy was indicated. Intraoperatively, extremely dilated loops of small and large intestine up to the distal sigmoid colon were noted. No anatomical or mechanical causes of obstruction were found. The postoperative course was complicated by dysfunctional intestinal motility and urinary catheter-related infection which required prokinetics and intravenous antibiotic therapy. The patient was transferred to a paediatric centre specialized in intestinal motility disorders for further treatment. Conclusion: This is the first case of intestinal pseudo-obstruction described as a part of clinical presentation of Kleefstra syndrome type 1. Further research and re-evaluation of patients with KS1 is needed to determine if intestinal pseudo-obstruction is a new clinical manifestation depending on the size of the deletion or a repercussion of hypotonia sequential to an underlying syndrome.

Identification of a Rare Novel KMT2C Mutation That Presents with Schizophrenia in a Multiplex Family

Schizophrenia is a complex genetic disorder involving many common variants with modest effects and rare mutations with high penetrance. Rare mutations associated with schizophrenia are highly heterogeneous and private for affected individuals and families. Identifying such mutations can help establish the molecular diagnosis, elucidate the pathogenesis, and provide helpful genetic counseling for affected patients and families. We performed a whole-exome sequencing analysis to search for rare pathogenic mutations co-segregating with schizophrenia transmitted in a dominant inheritance in a two-generation multiplex family. We identified a rare missense mutation H1574R (Histidine1574Arginine, rs199796552) of KMT2C (lysine methyltransferase 2C) co-segregating with affected members in this family. The mutation is a novel deleterious mutation of KMT2C, not reported before in the literature. The KMT2C encodes a histone 3 lysine 4 (H3K4)-specific methyltransferase and involves epigenetic regulation of brain gene expression. Mutations of KMT2C have been found in neurodevelopmental disorders, such as Kleefstra syndrome, intellectual disability, and autism spectrum disorders. Our finding suggests that schizophrenia might be one of the clinical phenotype spectra of KMT2C mutations, and KMT2C might be a novel risk gene for schizophrenia. Nevertheless, the co-segregation of this mutation with schizophrenia in this family might also be due to chance; functional assays of this mutation are needed to address this issue.

Dysregulation of NRSF/REST via EHMT1 is associated with psychiatric disorders

SummaryGenetic evidence indicates disrupted epigenetic regulation as a major risk factor for psychiatric disorders, but the molecular mechanisms that drive this association are undetermined. EHMT1 is an epigenetic repressor that is causal for Kleefstra Syndrome (KS), a neurodevelopmental disorder (NDD) leading to ID, and is associated with schizophrenia. Here, we show that reduced EHMT1 activity decreases NRSF/REST protein leading to abnormal neuronal gene expression and progression of neurodevelopment in human iPSC. We further show that EHMT1 regulates NRSF/REST indirectly via repression of miRNA leading to aberrant neuronal gene regulation and neurodevelopment timing. Expression of a NRSF/REST mRNA that lacks the miRNA-binding sites restores neuronal gene regulation to EHMT1 deficient cells. Importantly, the EHMT1-regulated miRNA gene set with elevated expression is enriched for NRSF/REST regulators with an association for ID and schizophrenia. This reveals a molecular interaction between H3K9 dimethylation and NSRF/REST contributing to the aetiology of psychiatric disorders.

The Impact of Rare Genetic Disorders on Family Functioning

The increasing presence of genetic neurodevelopmental disorders (NDDs) results in greater demands for counseling. Many studies focus on the characteristics of patients, but less on family functioning. The aim of this study is to objectify parental stress and to study its relationship with child characteristics and environmental factors across several syndromes. 56 individuals with NDD participated: 24 with Kleefstra Syndrome, 13 with Koolen-de Vries Syndrome, and 19 with other rare (mono) genetic disorders. Parents were asked to complete the General Functioning subscale of the Family Assessment Device (FAD-GF), the Child Behavioral Checklist, and a questionnaire about demographic parental data. 25.5% of the families scored above the cut-off for pathological stress (>2.17). The mean FAD–GF score was 1.84. There was no significant difference between mean FAD-score of the subgroups (p=0,70). (Para)medical counselors should address this high amount of parental stress during counseling and consider these genetic syndromes as complex chronical illnesses.

Prenatal diagnosis of Kleefstra syndrome

ObjectivesTo describe the prenatal diagnosis of Kleefstra syndrome (KS), a rare panethnic disorder characterized by mental and developmental delays, distinct facial features, congenital heart and urogenital defects, among others. KS is caused by haploinsusufficiency and loss of function of euchromatin histone methyltransferase 1 (EHMT1) due to deletions or mutations in the chromosomal region 9q34.3.Case presentationThe prenatal diagnosis of KS in this case report includes the description of subtle fetal phenotypic abnormalities detected by the fetal ultrasound examination as well as the results of the amniotic fluid microarray analysis that confirmed a fetal denovo deletion in the chromosomal region 9q34.3. These results confirmed the prenatal diagnosis of KS.ConclusionsThis case is noteworthy because of the late development of very subtle ultrasound abnormalities that triggered prenatal diagnostic studies in amniotic fluid cells, including SNP microarray analysis, that defined the diagnosis of KS. It allowed us to obtain the necessary antepartum consultations with neonatology, other pediatric subspecialties and arrange for the patient’s appropriate place of delivery to optimize the fetal and neonatal outcome.