Abstract
Zinc is an essential trace mineral. Dietary zinc deficiency results in stunted growth, skin lesions, hypogonadism and frequent infections in humans. Mice genetically lacking Slc30a7 suffer ...from mild zinc deficiency and are prone to development of prostate cancer and insulin resistance. Disease-causing variants or mutations in the human SLC30A7 (ZNT7) gene have not been previously reported. Here, we describe two-boy siblings from a French family with stunted growth, testicular hypoplasia and bone marrow failure. Exome sequencing revealed compound heterozygous variants in ZNT7 consisting of NM_133496.5:c.21dup; p.Asp8ArgfsTer3 and c.842 + 15 T > C inherited from their unaffected mother and father, respectively. The c.21dup variant led to a premature stop codon generated in exon 1 of the ZNT7 coding sequence. RNA-seq analysis demonstrated that the c.842 + 15 T > C variant resulted in a leaky mRNA splicing event generating a premature stop codon right after the splicing donor site of exon 8. Moreover, the expression of ZNT7 protein was remarkably reduced by 80–96% in the affected brothers compared to the control cells. These findings strongly suggest that biallelic variants in SLC30A7 should be considered as a cause of growth retardation, testicular hypoplasia and syndromic bone marrow failure.
Obtaining a rapid etiological diagnosis for infants with early-onset rare diseases remains a major challenge. These diseases often have a severe presentation and unknown prognosis, and the genetic ...causes are very heterogeneous. In a French hospital network, we assessed the feasibility of performing accelerated trio-genome sequencing (GS) with limited additional costs by integrating urgent requests into the routine workflow. In addition to evaluating our capacity for such an approach, this prospective multicentre pilot study was designed to identify pitfalls encountered during its implementation. Over 14 months, we included newborns and infants hospitalized in neonatal or paediatric intensive care units with probable genetic disease and in urgent need for etiological diagnosis to guide medical care. The duration of each step and the pitfalls were recorded. We analysed any deviation from the planned schedule and identified obstacles. Trio-GS was performed for 37 individuals, leading to a molecular diagnosis in 18/37 (49%), and 21/37 (57%) after reanalysis. Corrective measures and protocol adaptations resulted in a median duration of 42 days from blood sampling to report. Accelerated trio-GS is undeniably valuable for individuals in an urgent care context. Such a circuit should coexist with a rapid or ultra-rapid circuit, which, although more expensive, can be used in particularly urgent cases. The drop in GS costs should result in its generalized use for diagnostic purposes and lead to a reduction of the costs of rapid GS.
The purpose of this study is to describe a Mendelian disorder of DNA damage repair. Phenotypic delineation of two families, one new and one previously published, with overlapping dysmorphic and ...neurodevelopmental features was undertaken. Functional characterization of DNA damage repair in fibroblasts obtained from the index individuals in each of the two families was pursued. We present new evidence of a distinct disorder caused by biallelic truncating variants in
ZNF668
comprising microcephaly, growth deficiency, severe global developmental delay, brain malformation, and distinct facial dysmorphism. DNA damage repair defect was observed in fibroblasts of affected individuals. ZNF668 deficiency in humans results in a recognizable autosomal recessive disorder, which we propose to name
ZNF668
-related ZMAND (ZNF668-related brain malformation, microcephaly, abnormal growth, neurodevelopmental delay, and dysmorphism). Our results add to the growing list of Mendelian disorders of the DNA damage repair machinery.
Keratinocyte differentiation factor (KDF)1 has been shown to cause ectodermal dysplasia with or without hidradenitis suppurativa in a single family. KDF1 is known to regulate epidermal ...differentiation through its interaction with IκB kinase (IKK)α. We report a novel de novo KDF1 variant (p.His254Tyr) in a 20-year-old male patient presenting with hidradenitis suppurativa and ectodermal dysplasia. We demonstrate that variants in KDF1 associated with hidradenitis suppurativa actually cause pathogenic gain-of-function of KDF1 through upregulation of IKKα. Ectodermal dysplasia may be present in a subset of individuals with hidradenitis suppurativa and should be investigated. Inhibition of IKKα appears to be a suitable therapeutic target for these individuals.
Mitochondrial diseases (MDs) are a group of clinically heterogeneous genetic disorders that arise as the result of dysfunctional mitochondria. Only few medical articles deal with neuropsychological ...or psychiatric aspects of MDs.
The present article aims to provide a systematic review of neuropsychological and psychiatric aspects of MDs.
In order to identify all studies dealing with psychiatric and neuropsychological aspects of MDs in children and adolescents, we performed a search in the medical literature between April 2009 and April 2019 using PubMed, Cochrane, and Web of Science and we defined inclusion and exclusion criteria.
We found only seven studies that satisfy the inclusion requirements and criteria. The main psychiatric aspects reported in MDs were depressive and behavioral disorders. With regard to the neuropsychological aspects of MDs, developmental analyses showed an overall deterioration and developmental delay.
Children and adolescents with MDs may present psychiatric symptoms and neuropsychological impairment. A more systematic investigation of psychiatric and neuropsychological features of MDs is needed to foster a better understanding of the phenotype of these diseases and their links with the genotype, which may have significant implications for the developmental trajectories of patients.
Deoxyhypusine hydroxylase (DOHH) is the enzyme catalyzing the second step in the post-translational synthesis of hypusine Nε-(4-amino-2-hydroxybutyl)lysine in the eukaryotic initiation factor 5A ...(eIF5A). Hypusine is formed exclusively in eIF5A by two sequential enzymatic steps catalyzed by deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). Hypusinated eIF5A is essential for translation and cell proliferation in eukaryotes, and all three genes encoding eIF5A, DHPS, and DOHH are highly conserved throughout eukaryotes. Pathogenic variants affecting either DHPS or EIF5A have been previously associated with neurodevelopmental disorders. Using trio exome sequencing, we identified rare bi-allelic pathogenic missense and truncating DOHH variants segregating with disease in five affected individuals from four unrelated families. The DOHH variants are associated with a neurodevelopmental phenotype that is similar to phenotypes caused by DHPS or EIF5A variants and includes global developmental delay, intellectual disability, facial dysmorphism, and microcephaly. A two-dimensional gel analyses revealed the accumulation of deoxyhypusine-containing eIF5A eIF5A(Dhp) and a reduction in the hypusinated eIF5A in fibroblasts derived from affected individuals, providing biochemical evidence for deficiency of DOHH activity in cells carrying the bi-allelic DOHH variants. Our data suggest that rare bi-allelic variants in DOHH result in reduced enzyme activity, limit the hypusination of eIF5A, and thereby lead to a neurodevelopmental disorder.
This article describes mutations in DOHH as a cause of intellectual disability. These mutations decrease the activity of the eIF5A protein, whose dysfunction is known to cause intellectual disability.
Anoctamins are a family of Ca2+-activated proteins that may act as ion channels and/or phospholipid scramblases with limited understanding of function and disease association. Here, we identified ...five de novo and two inherited missense variants in ANO4 (alias TMEM16D) as a cause of fever-sensitive developmental and epileptic or epileptic encephalopathy (DEE/EE) and generalized epilepsy with febrile seizures plus (GEFS+) or temporal lobe epilepsy. In silico modeling of the ANO4 structure predicted that all identified variants lead to destabilization of the ANO4 structure. Four variants are localized close to the Ca2+ binding sites of ANO4, suggesting impaired protein function. Variant mapping to the protein topology suggests a preliminary genotype-phenotype correlation. Moreover, the observation of a heterozygous ANO4 deletion in a healthy individual suggests a dysfunctional protein as disease mechanism rather than haploinsufficiency. To test this hypothesis, we examined mutant ANO4 functional properties in a heterologous expression system by patch-clamp recordings, immunocytochemistry, and surface expression of annexin A5 as a measure of phosphatidylserine scramblase activity. All ANO4 variants showed severe loss of ion channel function and DEE/EE associated variants presented mild loss of surface expression due to impaired plasma membrane trafficking. Increased levels of Ca2+-independent annexin A5 at the cell surface suggested an increased apoptosis rate in DEE-mutant expressing cells, but no changes in Ca2+-dependent scramblase activity were observed. Co-transfection with ANO4 wild-type suggested a dominant-negative effect. In summary, we expand the genetic base for both encephalopathic sporadic and inherited fever-sensitive epilepsies and link germline variants in ANO4 to a hereditary disease.
This paper establishes missense variants in the anoctamin family member ANO4 (or TMEM16D) as a cause of distinct epileptic disorders. Resulting phenotypes depend on the location in the protein and the functional impact of the substitution such as loss of cation channel function and increased apoptosis signaling.
Mitochondrial disorders (MD) are a group of clinically heterogeneous genetic disorders resulting from dysfunction of the mitochondrial respiratory chain. Cognitive impairment is a common feature in ...adults with MD and psychiatric symptoms are associated with MD in up to 70% of the adult population. The aim of this study is to describe the psychiatric profile in children and adolescents with MD by focusing on the description of psychiatric symptoms.
A cohort of 12 children and adolescents was prospectively recruited between February 2019 and February 2020 in the Reference Center for Mitochondrial Disorders of Angers (France). Participants and their parents completed an anamnestic form to provide socio-demographic data and completed the Global Assessment of Functioning scale, the Brief Psychiatric Rating Scale, the Child Depression Inventory, the Revised Children's Manifest Anxiety Scale, and the Conner's Rating Scale to evaluate the inattention/hyperactivity symptoms as well as the Quality of Life scale.
Four children (33.3%) were diagnosed with depressive symptoms. With regarding to anxiety, 6 children (50%) reported anxiety issues during the psychiatric interview and 3 children (25%) were suffering from anxiety according to the RCMAS scale. Compared to other children with chronic illnesses, the individuals in our cohort reported a lower overall quality of life score and lower scores in physical and social subscales.
Our study shows that MD can lead to psychiatric disorders in children and adolescents, in particular anxiety and depression, as well as poor quality of life. This highlights the need for regular psychiatric assessments in individuals with developing brains, such as children and adolescents. We do not, however, have data regarding the neuropsychological profile of this population.
Recent identification of four additional polyaminopathies, including Bachmann-Bupp syndrome, have benefited from previous research on Snyder-Robinson syndrome in order to advance from research to ...treatment more quickly. As a result of the discovery of these conditions, the potential for treatment within this pathway, and for other possible unidentified polyaminopathies, the International Center for Polyamine Disorders (ICPD) was created to help promote understanding of these conditions, research opportunities, and appropriate care for families. This case study provides insights from two new patients diagnosed with Bachmann-Bupp syndrome, further expanding our understanding of this ultra-rare condition, as well as a general discussion about other known polyaminopathies. This work also presents considerations for collaborative research efforts across these conditions, along with others that are likely to be identified in time, and outlines the role that the ICPD hopes to fill as more patients with these polyaminopathies continue to be identified and diagnosed.
Pathogenic variants in genes encoding ubiquitin E3 ligases are known to cause neurodevelopmental syndromes. Additional neurodevelopmental disorders associated with the other genes encoding E3 ligases ...are yet to be identified.
Chromosomal analysis and exome sequencing were used to identify the genetic causes in 10 patients from 7 unrelated families with syndromic neurodevelopmental, seizure, and movement disorders and neurobehavioral phenotypes.
In total, 4 patients were found to have 3 different homozygous loss-of-function (LoF) variants, and 3 patients had 4 compound heterozygous missense variants in the candidate E3 ligase gene, HECTD4, that were rare, absent from controls as homozygous, and predicted to be deleterious in silico. In 3 patients from 2 families with Angelman-like syndrome, paralog-directed candidate gene approach detected 2 LoF variants in the other candidate E3 ligase gene, UBE3C, a paralog of the Angelman syndrome E3 ligase gene, UBE3A. The RNA studies in 4 patients with LoF variants in HECTD4 and UBE3C provided evidence for the LoF effect.
HECTD4 and UBE3C are novel biallelic rare disease genes, expand the association of the other HECT E3 ligase group with neurodevelopmental syndromes, and could explain some of the missing heritability in patients with a suggestive clinical diagnosis of Angelman syndrome.
PDF
