Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Poznan, Poland.
Non-syndromic cleft lip with or without cleft palate (nsCL/P) is a common craniofacial anomaly with a complex and heterogeneous etiology. Knowledge regarding specific genetic factors underlying this birth defect is still not well understood. Therefore, we conducted an independent replication analysis for the top-associated variants located within the DLG1 locus at chromosome 3q29, which was identified as a novel cleft-susceptibility locus in our genome-wide association study (GWAS). Read More
Leigh syndrome (LS) is an inherited mitochondrial encephalopathy associated with gene mutations of oxidative phosphorylation(OXPHOS) pathway that result in early disability and death in affected young children. Currently, LS is incurable and unresponsive to many treatments, although some case reports indicate that supplements can improve the condition. Many novel therapies are being continuously tested in preclinical studies. Read More
Acephalic spermatozoa is a rare teratozoospermia associated with male infertility. However, the pathogenesis of this disorder remains unclear. Here, we report a 27-year-old infertile male from a consanguineous family, who presented with 99% headless sperm in his ejaculate. Read More
Uveal melanoma (UM) is the most frequent primary intraocular tumor in Caucasian adults and is potentially fatal if metastases develop. While several prognostic genetic changes have been identified in UM, epigenetic influences are now getting closer attention. Recent technological advances have allowed to examine the human genome to a greater extent and have improved our understanding of several diseases including malignant tumors. Read More
Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyze the transfer of methyl groups from S-adenosyl-l-methionine to nitrogen atoms on arginine residues. Arginine methylation is involved in multiple biological processes, such as signal transduction, mRNA splicing, transcriptional control, DNA repair, and protein translocation. Currently, seven patients have been described harboring compound heterozygous or homozygous variants in the PRMT7 gene, causing a novel intellectual disability syndrome, known as SBIDDS syndrome (Short Stature, Brachydactyly, Intellectual Developmental Disability, and Seizures). Read More
Smith-Kingsmore syndrome (SKS) OMIM #616638, also known as MINDS syndrome (ORPHA: 457485), is a rare autosomal dominant disorder reported so far in 23 patients. SKS is characterized by intellectual disability, macrocephaly/hemi/megalencephaly, and seizures. It is also associated with a pattern of facial dysmorphology and other non-neurological features. Read More
Beukes Hip Dysplasia is an autosomal dominant disease which has to date been described only in a large South African family of Dutch origin. The patients presented with progressive epiphyseal dysplasia limited to femoral capital epiphysis and their height was not significantly reduced. A unique variant of the ubiquitin-fold modifier 1 (Ufm1)-specific peptidase 2 (UFSP2) gene (c. Read More
Diagnostic exome sequencing (DES) has aided delineation of the phenotypic spectrum of rare genetic etiologies of intellectual disability (ID). A SETD5 phenotype of ID and dysmorphic features has been previously described in relation to patients with 3p25.3 deletions and in a few individuals with de novo sequence alterations. Read More
Parkinson's disease (PD) is a genetically heterogeneous disorder and new putative disease genes are discovered constantly. Therefore, whole exome sequencing could be an efficient approach to genetic testing in PD. To evaluate its performance in early-onset sporadic PD, we performed diagnostic exome sequencing in 80 individuals with manifestation of PD symptoms at age 40 or earlier and a negative family history of PD. Read More
Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
Deficiencies of mitochondrial respiratory chain complex I frequently result in leukoencephalopathy in young patients, and different mutations in the genes encoding its subunits are still being uncovered. We report two patients with cystic leukoencephalopathy and complex I deficiency with recessive mutations in NDUFA2, an accessory subunit of complex I. The first patient was initially diagnosed with a primary systemic carnitine deficiency associated with a homozygous variant in SLC22A5, but also exhibited developmental regression and cystic leukoencephalopathy, and an additional diagnosis of complex I deficiency was suspected. Read More
The lack of a validated severity scoring system for individuals with Zellweger spectrum disorders (ZSD) hampers optimal patient care and reliable research. Here, we describe the development of such severity score and its validation in a large, well characterized cohort of ZSD individuals. We developed a severity scoring system based on the 14 organs that typically can be affected in ZSD. Read More
Medical Genetics Unit, A.O.R.N. "G. Rummo", Benevento, Italy.
The Say-Barber-Biesecker-Young-Simpson variant of Ohdo syndrome (SBBYSS) and Genitopatellar syndrome (GTPTS) are two rare but clinically well-described diseases caused by de novo heterozygous sequence variants in the KAT6B gene. Both phenotypes are characterized by significant global developmental delay/intellectual disability, hypotonia, genital abnormalities, and patellar hypoplasia/agenesis. In addition, congenital heart defects, dental abnormalities, hearing loss, and thyroid anomalies are common to both phenotypes. Read More
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, 00146, Rome, Italy.
Ellis van Creveld syndrome (EvC) is a chondral and ectodermal dysplasia caused by biallelic mutations in the EVC, EVC2 and WDR35 genes. A proportion of cases with clinical diagnosis of EvC, however, do not carry mutations in these genes. To identify the genetic cause of EvC in a cohort of mutation-negative patients, exome sequencing was undertaken in a family with three affected members, and mutation scanning of a panel of clinically and functionally relevant genes was performed in 24 additional subjects with features fitting/overlapping EvC. Read More
Inherited bone marrow failure syndromes (IBMFS) are group of disorders that lead to inadequate production of blood cells. Mutations in genes involved in telomere maintenance, DNA repair, and the cell cycle cause IBMFS. ERCC6L2 gene mutations have been associated with bone marrow failure that includes developmental delay and microcephaly. Read More
Gene-panel sequencing allows comprehensive analysis of multiple genes simultaneously and is now routinely used in clinical mutation testing of high-risk breast and ovarian cancer patients. However, only BRCA1 and BRCA2 are often analyzed also for large genomic changes. Here, we have analyzed 10 clinically relevant susceptibility genes in 95 breast or ovarian cancer patients with gene-panel sequencing including also CNV analysis for genomic changes. Read More
SATB2-associated syndrome (SAS) is a rare disorder caused by alterations in the special AT-rich sequence-binding protein 2 (SATB2). Skeletal abnormalities such as tibial bowing, osteomalacia, osteopenia or osteoporosis have been reported suggesting a higher frequency of skeletal complications in SAS. The optimal timing, necessity, and methodology for routine assessment of bone health in individuals with SAS, however, remain unclear. Read More
We report a consanguineous Arab family with three affected siblings who display a disorder of global developmental delay, learning difficulties, facial dysmorphism, hearing impairments, and cataract. The clinical phenotype was associated with characteristic brain Magnetic Resonance Imaging (MRI) features of axonal guidance defects involving anterior commissure agenesis as well as scattered areas of polymicrogyria-cobblestone complex. Whole genome sequencing revealed a novel nonsense mutation (159609921C>T) that segregated in the family consistent in an autosomal recessive pattern. Read More
Department of Kidney, Liver and Metabolic Disease, Division of Pediatric Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany.
Next-Generation Sequencing (NGS) has opened up novel diagnostic opportunities for children with unidentified, but suspected inherited diseases. We describe our single-center experience with NGS diagnostics in standard clinical scenarios in pediatric hepatology. We investigated 135 children with suspected inherited hepatopathies, where initially no causative pathogenic variant had been identified, with an amplicon-based NGS panel of 21 genes associated with acute and chronic hepatopathies. Read More
Genetic dominance has long been considered as a qualitative reflection of interallelic interactions. Dominance arises from many multiple sources whose unifying theme is the existence of non-linear relationships between the genotypic and phenotypic values. One of the clearest examples are dominant negative mutations (DNMs) in which a defective subunit poisons a macromolecular complex. Read More
Inserm-UMRS 954 (Nutrition-Genetics-Environmental Risks) and National reference centre for inherited metabolic diseases, University of Lorraine and University Regional Hospital Center, 54500, Vandoeuvre lès Nancy, France.
Folate and vitamin B12 are needed for the proper embryo-fetal development possibly through their interacting role in the one-carbon metabolism. Folate fortification reduces the prevalence of complex birth defects, and more specifically neural tube defects (NTD). GIF and FUT2 are two genes associated with the uptake and blood level of vitamin B12. Read More
A 28-year-old female with PIK3CA-related segmental overgrowth presented with headaches. She also had a unilateral vestibular schwannoma (VS), as well as three small (<2 cm) meningiomas, which according to the Manchester consensus diagnostic criteria for neurofibromatosis 2 (NF2) is sufficient for a clinical diagnosis. Analysis of blood revealed a mosaic PIK3CA c. Read More
Though whole exome sequencing is the gold standard for the diagnosis of neurodevelopmental disorders, it remains expensive for some genetic centers. Commercialized panels comprising all OMIM-referenced genes called "medical exome" constitute an alternative strategy to whole exome sequencing, but its efficiency is poorly known. In this study, we report the experience of two clinical genetic centers using medical exome for diagnosis of neurodevelopmental disorders. Read More
The inherited peripheral neuropathies (IPNs) are characterized by marked clinical and genetic heterogeneity and include relatively frequent presentations such as Charcot-Marie-Tooth disease and hereditary motor neuropathy, as well as more rare conditions where peripheral neuropathy is associated with additional features. There are over 250 genes known to cause IPN-related disorders but it is estimated that in ~50% of affected individuals a molecular diagnosis is not achieved. In this study, we examine the diagnostic utility of whole-exome sequencing (WES) in a cohort of 50 families with one or more affected individuals with a molecularly undiagnosed IPN with or without additional features. Read More
PEDEGO Research Unit, University of Oulu, Oulu, Finland.
Mitochondria produce adenosine triphosphate (ATP) for energy requirements via the mitochondrial oxidative phosphorylation (OXPHOS) system. One of the hallmarks of cancer is the energy shift towards glycolysis. Low OXPHOS activity and increased glycolysis are associated with aggressive types of cancer. Read More
Single-nucleotide polymorphism (SNP)-based noninvasive prenatal testing (NIPT) can currently predict a subset of submicroscopic abnormalities associated with severe clinical manifestations. We retrospectively analyzed the performance of SNP-based NIPT in 80,449 referrals for 22q11.2 deletion syndrome and 42,326 referrals for 1p36, cri-du-chat, Prader-Willi, and Angelman microdeletion syndromes over a one-year period, and compared the original screening protocol with a revision that reflexively sequenced high-risk calls at a higher depth of read. Read More
Patients suffering from psychiatric disorders have a life span burden, which represents an enormous human, family, social, and economical cost. Several concepts have revolutionized our way of appraising neuropsychiatric disorders (NPDs). They result from a combination of genetic factors and environmental insults, and their etiology finds roots in the neurodevelopmental period. Read More
Mutations in valosin-containing protein (VCP), an ATPase involved in protein degradation and autophagy, cause VCP disease, a progressive autosomal dominant adult onset multisystem proteinopathy. The goal of this study is to examine if phenotypic differences in this disorder could be explained by the specific gene mutations. We therefore studied 231 individuals (118 males, 113 females) from 36 families carrying 15 different VCP mutations. Read More
North West Thames Regional Genetics Service, London North West Healthcare NHS Trust, Harrow, UK.
Rare de novo mutations represent a significant cause of idiopathic developmental delay. The use of NGS has boosted the identification of de novo mutations in an increasing number of novel genes. Here we present three unrelated children with de novo LoF mutations in QRICH1, diagnosed through trio exome sequencing. Read More
Mitochondrial disorders (MDs) are caused by defects in one or multiple complexes of the oxidative phosphorylation (OXPHOS) machinery. MDs are associated with a broad range of clinical signs and symptoms, and have considerable clinical overlap with other neuromuscular syndromes. This overlap might be due to involvement of mitochondrial pathways in some of these non-mitochondrial syndromes. Read More
Glycogen storage disease (GSD) type I is inborn metabolic disease characterized by accumulation of glycogen in multiple organs. We analyzed 38 patients with clinical suspicion of GSD I using Sanger and next-generation sequencing (NGS). We identified 28 GSD Ib and five Ia patients. Read More
Computer and Systems Engineering Department, Alexandria University, Alexandria, Egypt.
Integrative approaches that combine multiple forms of data can more accurately capture CGEway associations and so provide a comprehensive understanding of the molecular mechanisms that cause complex diseases. Association analyses based on SNP genotypes, CNV genotypes, and gene expression profiles are the three most common paradigms used for gene set/ CGEway enrichment analyses. Many work has been done to leverage information from two types of data from these three paradigms. Read More
The phenotypic spectrum associated with heterozygous mutations in cartilage oligomeric matrix protein gene (COMP) range from a mild form of multiple epiphyseal dysplasia (MED) to pseudoachondroplasia (PSACH). However, the phenotypic effect from biallelic COMP variants is unclear. We investigated a large consanguineous Pakistani family with a severe form of PSACH in two individuals. Read More
IBA57 is involved in the biogenesis of mitochondrial [4Fe-4S] proteins. Eighteen cases with IBA57 mutations have been reported to date. We described a novel phenotype in 11 children with cavitating leukoencephalopathy and summarized the phenotypic spectrum of IBA57 mutations. Read More
Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, 28049 Madrid/Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Investigación Sanitaria IdiPAZ, Madrid, Spain.
Protein misfolding has been linked to numerous inherited diseases. Loss- and gain-of-function mutations (common features of genetic diseases) may cause the destabilization of proteins, leading to alterations in their properties and/or cellular location, resulting in their incorrect functioning. Misfolded proteins can, however, be rescued via the use of proteostasis regulators and/or pharmacological chaperones, suggesting that treatments with small molecules might be developed for a range of genetic diseases. Read More
Mitochondrial respiratory chain complex I consists of 44 different subunits and contains three functional modules: the Q-, the N- and the P-module. NDUFA9 is a Q-module subunit required for complex I assembly or stability. However, its role in complex I biogenesis has not been studied in patient fibroblasts. Read More
High throughput approaches are continuously progressing and have become a major part of clinical diagnostics. Still, the critical process of detailed phenotyping and gathering clinical information has not changed much in the last decades. Forms of Next Generation Phenotyping (NGP) are needed to increase further the value of any kind of genetic approaches, including timely considering of (molecular) cytogenetics during the diagnostic quest. Read More
Otofaciocervical syndrome is a rare disorder characterized by facial anomalies, cup-shaped low-set ears, preauricular fistulas, hearing loss, branchial defects, skeletal anomalies, and mild intellectual disability. Autosomal dominant cases are caused by deletions or point mutations of EYA1. A single family with an autosomal recessive form of otofaciocervical syndrome and a homozygous missense mutation in PAX1 gene has been described. Read More
Menkes disease is a lethal disorder characterized by severe neurological symptoms and connective tissue abnormalities; and results from malfunctioning of cuproenzymes, which cannot receive copper due to a defective intracellular copper transporting protein, ATP7A. Early parenteral copper-histidine supplementation may modify disease progression substantially but beneficial effects of long-term treatment have been recorded in only a few patients. Here we report on the eldest surviving Menkes disease patient (37 years) receiving early-onset and long-term copper treatment. Read More
Mutations in GLE1, RNA export mediator (GLE1) gene have previously been shown to cause motor neuron diseases such as Lethal congenital contracture syndrome 1 (LCCS1) and Lethal arthrogryposis with anterior horn cell disease (LAAHD), including arthrogryposis, fetal akinesis and motor neuron loss as common clinical features. The homozygous FinMajor mutation p.T144_E145insPFQ has been described as one of the causes for LCCS1 whereas LAAHD is caused by a heterocompound FinMajor mutation together with p. Read More
Biallelic mutations in SLC25A46, encoding a modified solute transporter involved in mitochondrial dynamics, have been identified in a wide range of conditions such as hereditary motor and sensory neuropathy with optic atrophy type VIB (OMIM: *610826) and congenital lethal pontocerebellar hypoplasia (PCH). To date, 18 patients from 13 families have been reported, presenting with the key clinical features of optic atrophy, peripheral neuropathy, and cerebellar atrophy. The course of the disease was highly variable ranging from severe muscular hypotonia at birth and early death to first manifestations in late childhood and survival into the fifties. Read More
Cystinuria is a heterogeneous, rare but important cause of inherited kidney stone disease due to mutations in two genes: SLC3A1 and SLC7A9. Antenatal hyperechoic colon has been reported in some patients as a non-pathological consequence of the intestinal transport defect. We report 83 patients affected by cystinuria: 44 presented prenatally with a hyperechoic colon (HEC group) and 39 with a classical postnatal form (CC group). Read More
Mutations in Plastin-3 (PLS3) have been identified as a cause of X-linked osteoporosis. To reveal the molecular mechanism of PLS3 on osteoporosis, we characterized the p.Ala253_Leu254insAsn mutation in PLS3. Read More
Congenital Adrenal Hyperplasia due to 21-hydroxylase deficiency (21OHD-CAH) is an autosomal recessive disorder affecting steroidogenesis, due to mutations in CYP21A2 (6p21.3). 21OHD-CAH neonatal screening is based on 17-hydroxyprogesterone (17OHP) serum levels, showing high type I error rate and low sensitivity to mild CAH forms. Read More
Familial microscopic hematuria (FMH) is associated with a genetically heterogeneous group of conditions including the collagen-IV nephropathies, the heritable C3/CFHR5 nephropathy and the glomerulopathy with fibronectin deposits. The clinical course varies widely, ranging from isolated benign familial hematuria to end-stage renal disease (ESRD) later in life. We investigated 24 families using Next Generation Sequencing (NGS) for five genes: COL4A3, COL4A4, COL4A5, CFHR5 and FN1. Read More
Lynch Syndrome (LS) mutation carriers may reduce their cancer risk by adhering to lifestyle recommendations for cancer prevention. This study tested the effect of providing LS mutation carriers with World Cancer Research Fund (WCRF)-NL health promotion materials on awareness and knowledge of and adherence to these recommendations. In this randomized controlled trial (n = 226), the intervention group (n = 114) received WCRF-NL health promotion materials. Read More
Microcephalic primordial dwarfisms are a group of rare Mendelian disorders characterized by severe growth retardation and microcephaly. The molecular basis is heterogeneous, with disease-causing genes implicated in different cellular functions. Recently, 2 patients were reported with the same homozygous variant in the WDR4 gene, coding for an enzyme responsible for the m(7) G46 post transcriptional modification of tRNA. Read More
Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability and the leading form of the monogenic cause of autism. FMR1 premutation is the first single-gene cause of primary ovarian failure (FXPOI) and one of the most common causes of ataxia (FXTAS), multiple additional phenotypes such as fibromyalgia, hypothyroidism, migraine headaches, sleep disturbances, sleep apnea, restless legs syndrome, central pain syndrome, neuropathy and neuropsychiatric alterations has been described. Clinical involvement in men and women carrying the FMR1 premutation currently constitutes a real health problem in the society that should be taken into account. Read More