Intragenic CNTN4 copy number variants associated with a spectrum of neurobehavioral phenotypes.
In this study, we performed clinical and genetic characterization of three individuals from unrelated families with copy number variants (CNV) (one deletion and two duplications) within CNTN4. The patients exhibited cognitive delay (3/3), growth restriction (3/3), motor delay (2/3), and febrile seizure/epilepsy (2/3). In contrast to previous reports, all probands presented with speech apraxia or delay with no diagnosis of ASD. Parental studies for the proband with the deletion and one of the 2 probands with the duplication revealed paternal origin of the CNTN4 CNV. Interestingly, previously documented CNV involving this ge...
Source: European Journal of Medical Genetics - August 15, 2019 Category: Genetics & Stem Cells Authors: Zhang SQ, Fleischer J, Al-Kateb H, Mito Y, Amarillo I, Shinawi M Tags: Eur J Med Genet Source Type: research

First report of THOC6 related intellectual disability (Beaulieu Boycott Innes syndrome) in two siblings from India.
This report reviews the phenotypic and genetic data of known BBIS cases in addition to the new phenotypic features, thereby expanding the phenotype of this rare syndrome. PMID: 31421288 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - August 14, 2019 Category: Genetics & Stem Cells Authors: Gupta N, Yadav S, Gurramkonda VB, Vl R, Sg T, Kabra M Tags: Eur J Med Genet Source Type: research

Striking phenotypic overlap between Nicolaides-Baraitser and Coffin-Siris syndromes in monozygotic twins with ARID1B intragenic deletion.
Abstract The chromatin remodeling AT-Rich interaction domain containing 1B protein (ARID1B) also known as BAF-associated factor, 250-KD, B (BAF250B) codified by the ARID1B gene (MIM#614556), is a small subunit of the mammalian SWI/SNF or BAF complex, an ATP-dependent protein machinery which is able to activate or repress gene transcription, allowing protein access to histones through DNA relaxed conformation. ARID1B gene mutations have been associated with two hereditary syndromic conditions, namely Coffin-Siris (CSS, MIM#135900) and Nicolaides-Baraitser syndromes (NCBRS, MIM#601358), characterized by neurodevelop...
Source: European Journal of Medical Genetics - August 14, 2019 Category: Genetics & Stem Cells Authors: Pascolini G, Valiante M, Bottillo I, Laino L, Fleischer N, Ferraris A, Grammatico P Tags: Eur J Med Genet Source Type: research

A classification system for split-hand/ foot malformation (SHFM): A proposal based on 3 pedigrees with WNT10B mutations.
Abstract SHFM6 (OMIM 225300) is caused by WNT10B pathogenic variants (12q13.12). It is one of the rarest forms of SHFM; with only seven pathogenic variants described in the world literature. Furthermore, it has not been determined if SHFM6 has specific phenotypic characteristics. In this paper, we present a case series of three unrelated families with SHFM6 caused by three novel WNT10B pathogenic variants. The index patient of the first family was homozygous for the nonsense variant c.676C > T (p.Arg226*) in the WNT10B gene. The index case of the second family had a homozygous splice variant c.338-1G...
Source: European Journal of Medical Genetics - August 14, 2019 Category: Genetics & Stem Cells Authors: Al Ghamdi MA, Al-Qattan MM, Hadidi A, Alabdulrahman A, Almuzzaini B, Alatwi N, AlBalwi MA Tags: Eur J Med Genet Source Type: research

Mild macrocytosis in Williams-Beuren syndrome.
CONCLUSIONS: Mild macrocytosis without anemia affects a moderate subset of WBS patients, leading to a rightward shift in the MCV distribution curve. Providers encountering isolated mild macrocytosis in WBS can consider observation over further workup. PMID: 31419598 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - August 13, 2019 Category: Genetics & Stem Cells Authors: Yu E, Feinn R, Bona R, Brink B, Sindhar S, Kozel B, Pober BR Tags: Eur J Med Genet Source Type: research

DNA methylation fingerprint of monozygotic twins and their singleton sibling with intellectual disability carrying a novel KDM5C mutation.
Abstract Mutations in KDM5C (lysine (K)-specific demethylase 5C) were causally associated with up to 3% of X-linked intellectual disability (ID) in males. By exome and Sanger sequencing, a novel frameshift KDM5C variant, predicted to eliminate the JmjC catalytic domain from the protein, was identified in two monozygotic twins and their older brother, which was inherited from their clinically normal mother, who had completely skewed X-inactivation. DNA methylation (DNAm) data were evaluated using the Illumina 450 K Methylation Beadchip arrays. Comparison of methylation levels between the three patients and male c...
Source: European Journal of Medical Genetics - August 13, 2019 Category: Genetics & Stem Cells Authors: Guerra JVS, Oliveira-Santos J, Oliveira DF, Leal GF, Oliveira JRM, Costa SS, Krepischi ACV, Vianna-Morgante AM, Maschietto M Tags: Eur J Med Genet Source Type: research

Genotype-phenotype correlation: Inheritance and variant-type infer pathogenicity in IQSEC2 gene.
We present male (N = 2) and female (N = 3) probands ascertained via diagnostic exome sequencing with distinct variant types in the IQSEC2 gene encompassing a spectrum of phenotypic severity with patient sex, variant type and inheritance hypothesized to drive disease penetrance and expressivity. All of these patients demonstrated epilepsy, global developmental delays, intellectual disability, and constipation. Our data support that de novo, truncating variants correlate with severe disease in both female and male patients harboring an IQSEC2 alteration. Missense variants in male and female patients may account for a...
Source: European Journal of Medical Genetics - August 12, 2019 Category: Genetics & Stem Cells Authors: Barrie ES, Cottrell CE, Gastier-Foster J, Hickey SE, Patel AD, Santoro SL, Alfaro MP Tags: Eur J Med Genet Source Type: research

Clinical benefits of preimplantation genetic testing for aneuploidy (PGT-A) for all in vitro fertilization treatment cycles.
Abstract The clinical application of a PGT-A program implementing single euploid embryo transfer is evaluated over a 6.5 year period, beginning with its early validation phases. Euploidy embryo status is inversely correlated to oocyte source age and positively correlated to blastocyst quality grades. However, once a single euploid embryo is transferred, high levels of implantation and live birth success are attained independent of patient age and embryo quality, with only AA blastocysts exhibiting improved implantation. Factors influencing successful outcomes are discussed, including the management of mosaic NGS p...
Source: European Journal of Medical Genetics - July 27, 2019 Category: Genetics & Stem Cells Authors: Anderson RE, Whitney JB, Schiewe MC Tags: Eur J Med Genet Source Type: research

Co-inheritance of pathogenic variants in PKD1 and PKD2 genes presenting as severe antenatal phenotype of autosomal dominant polycystic kidney disease.
We describe a family with recurrent foetal presentation of ADPKD due to co-inheritance of pathogenic variants in both PKD1 [c.3860T > C; p.(Leu1287Pro)] and PKD2 [(c.1000C > A; p.(Pro334Thr)] genes. Familial segregation studies revealed the mother and the father to be heterozygous for the same variants in the PKD1 and PKD2 genes, respectively, as found in the foetus. Renal ultrasonography detected evidence of cystic disease in the mother and two of her family members. No cysts were detected in the father, however the paternal grandfather died of renal cystic disease. The absence of disease in the father can b...
Source: European Journal of Medical Genetics - July 23, 2019 Category: Genetics & Stem Cells Authors: Arora V, Bijarnia-Mahay S, Tiwari V, Bansal S, Gupta P, Setia N, Puri RD, Verma IC Tags: Eur J Med Genet Source Type: research

BCAP31-related syndrome: The first de novo report.
Abstract Pathogenic variants in the BCAP31 gene have recently been associated with a severe congenital neurological phenotype, named DDCH after its key features: deafness, dystonia and central hypomyelination. BCAP31 is located at the Xq28 chromosomal region and only male individuals are currently known to be affected, the pathogenic variant being usually transmitted by healthy mothers. Here, we describe a three-year-old male child referred for severe developmental delay, failure to thrive, hearing loss and dyskinetic movements. After a conventional diagnostic workflow, including a normal array-CGH, a tentative di...
Source: European Journal of Medical Genetics - July 19, 2019 Category: Genetics & Stem Cells Authors: Rinaldi B, Van Hoof E, Corveleyn A, Van Cauter A, de Ravel T Tags: Eur J Med Genet Source Type: research

Novel pathogenic TGFBR1 and SMAD3 variants identified after cerebrovascular events in adult patients with Loeys-dietz syndrome.
CONCLUSION: LDS is characterized by genetic and clinical variability. Our report suggests that this genetically-determined connective tissue disorder is probably underestimated, as it might firstly show up with cerebrovascular events, although mild systemic manifestations. These findings could lead to identify people at risk of severe vascular complications (i.e., through genetic consult on asymptomatic relatives), in order to perform adequate vascular assessments and follow-up to prevent complications such as stroke. PMID: 31326520 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - July 18, 2019 Category: Genetics & Stem Cells Authors: Laterza D, Ritelli M, Zini A, Colombi M, Dell'Acqua ML, Vandelli L, Bigliardi G, Verganti L, Vallone S, Vincenzi C, Rosafio F, Ciolli L, Calabrese O, Nichelli PF, Picchetto L Tags: Eur J Med Genet Source Type: research

The utility of next generation sequencing in the correct diagnosis of congenital hypochloremic hypokalemic metabolic alkalosis.
Abstract Persistent hypokalemic hypochloremic metabolic alkalosis represents a heterogeneous group of genetic disorders of which the most common is Bartter syndrome (BS). BS is an inherited renal tubulopathy caused by defective salt reabsorption in the thick ascending loop of Henle, which results in persistent hypokalemic hypochloremic metabolic alkalosis. Here we report a 10-year-old girl of a consanguineous family. She presented prenatally with severe polyhydramnios and distended bowel loops. Thereafter, she displayed failure to thrive and had recurrent admissions due to dehydration episodes associated with diar...
Source: European Journal of Medical Genetics - July 17, 2019 Category: Genetics & Stem Cells Authors: Ben-David Y, Halevy R, Sakran W, Zehavi Y, Spiegel R Tags: Eur J Med Genet Source Type: research

A family with Classical Ehlers-Danlos Syndrome (cEDS), mild bone fragility and without vascular complications, caused by the p.Arg312Cys mutation in COL1A1.
In this report, we describe two patients from a large family with this mutation and clinical features consistent with cEDS without vascular complications. The proband presented with congenital hip dislocation (previously reported in one patient), the mother of the proband with multiple fractures in childhood, and dental defects (novel findings). The small number of patients reported with this mutation and proportion with vascular complications suggests that vascular surveillance should still be recommended. PMID: 31323331 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - July 16, 2019 Category: Genetics & Stem Cells Authors: Duong J, Rideout A, MacKay S, Beis J, Parkash S, Schwarze U, Horne G, Vandersteen A Tags: Eur J Med Genet Source Type: research

A novel truncating variant p.(Arg297*) in the GRM1 gene causing autosomal-recessive cerebellar ataxia with juvenile-onset.
We report a six-year-old boy, born to inbred parents, with an early-onset cerebellar syndrome due to a homozygous autosomal-recessive GRM1 pathogenic variant. In addition to cerebellar ataxia, axial hypotonia and oculomotor signs, he showed a severe and global developmental delay with lack of walking and speech and slight facial dysmorphic features. Brain MRI, performed at 1 year and at 5 years, showed a slowly progressive cerebellar atrophy. A novel homozygous truncating variant in the second exon of GRM1 gene (c.889C > T, p.(Arg297*)), inherited from the heterozygous healthy parents, was found by exome seque...
Source: European Journal of Medical Genetics - July 15, 2019 Category: Genetics & Stem Cells Authors: Cabet S, Putoux A, Carneiro M, Labalme A, Sanlaville D, Guibaud L, Lesca G Tags: Eur J Med Genet Source Type: research

Heterozygous FGFR1 mutation may be responsible for an incomplete form of osteoglophonic dysplasia, characterized only by radiolucent bone lesions and teeth retentions.
This report describes a mild form of OD and expands the phenotype related to FGFR1 mutations. These findings emphasize the need to consider FGFR1 variants in the case of multiple non-ossifying bone lesions associated with dental eruption anomalies. PMID: 31319224 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - July 15, 2019 Category: Genetics & Stem Cells Authors: Marzin P, Baujat G, Gensburger D, Huber C, Bole C, Panuel M, Finidori G, De la Dure M, Cormier-Daire V Tags: Eur J Med Genet Source Type: research

Clinical utility of a targeted next generation sequencing panel in severe and pediatric onset Mendelian diseases.
In conclusion, a targeted panel covering a high number of genes responsible for broad phenotypic spectrum can provide improved levels of diagnosis in patients with pediatric onset Mendelian diseases. A careful clinical evaluation of patients prior to the application of a next generation sequencing method leads to the best alternative approach for a conclusive molecular diagnosis. PMID: 31319225 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - July 15, 2019 Category: Genetics & Stem Cells Authors: Isik E, Onay H, Atik T, Canda E, Çoğulu O, Coker M, Ozkinay F Tags: Eur J Med Genet Source Type: research

Exome-wide copy number variation analysis identifies a COL9A1 in frame deletion that is associated with hearing loss.
a B Abstract Pathogenic variants in COL9A1 are primarily associated with autosomal recessive Stickler syndrome. Patients with COL9A1-associated Stickler syndrome present hearing loss (HL), ophthalmic manifestations and skeletal abnormalities. However, the clinical spectrum of patients with COL9A1 variants can also include multiple epiphyseal dysplasia, as well as non-syndromic HL that was observed in one previously reported proband. Exome sequencing was performed on the genomic DNA of an Iranian patient and his affected brother who both report non-syndromic HL. A 44.6 kb homozygous in-frame deletion spanning exo...
Source: European Journal of Medical Genetics - July 14, 2019 Category: Genetics & Stem Cells Authors: Hofrichter MAH, Doll J, Habibi H, Enayati S, Vahidi Mehrjardi MY, Müller T, Dittrich M, Haaf T, Vona B Tags: Eur J Med Genet Source Type: research

Mutation spectrum of MMACHC in Chinese pediatric patients with cobalamin C disease: A case series and literature review.
Abstract Cobalamin (cbl) C disease is a rare autosomal recessive inheritance disease, which is the most common cobalamin metabolic disorder. Its clinical phenotype involves multiple systems with varying degrees of severity, where in mild cases can be asymptomatic for many years, whereas severe cases may cause death during the neonatal period. The disease is caused by mutations in the MMACHC gene located on chromosome 1p34.1 that contains 5 exons; among which, exons 1-4 have an 849 bp coding sequence that encodes a protein containing 282 amino acids. Through clinical physical examination and laboratory tests, espec...
Source: European Journal of Medical Genetics - July 4, 2019 Category: Genetics & Stem Cells Authors: Wang C, Li D, Cai F, Zhang X, Xu X, Liu X, Zhang C, Wang D, Liu X, Lin S, Zhang Y, Shu J Tags: Eur J Med Genet Source Type: research

Early-onset stroke in two siblings with Neurofibromatosis type 1.
l C Abstract Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disorder, characterized by cafe-au-lait macules, benign neurofibromas as well as malignant peripheral nerve sheath tumours, freckling in the axillary or inguinal regions, optic glioma and Lisch nodules (iris hamartomas) and further manifestations like bone deformities etc. Additionally, NF1 patients are at increased risk of early-onset cerebrovascular diseases, the pathogenesis of which has not been clarified yet. Here we report the first case of two siblings with NF1 who suffered an acute ischemic stroke. Professionals treating NF...
Source: European Journal of Medical Genetics - July 4, 2019 Category: Genetics & Stem Cells Authors: Rukavina K, Töpper R, Kunze A, Hess A, Glatzel M, Valdueza JM, Farschtschi S, Hagel C Tags: Eur J Med Genet Source Type: research

Congenital Sodium Diarrhea by mutation of the SLC9A3 gene.
We report a male patient with typical antenatal symptoms (polyhydramnios and intestinal dilation) and neonatal diarrhea with fecal sodium and bicarbonates loss. Next generation sequencing revealed a missense homozygous mutation in exon 6 of the SLC9A3 gene (NM_004174.3:c.1039G > A, NP_004165.2:p.Glu347Lys). Oral electrolytes supplements (Sodium and Bicarbonates) allowed a normal growth to the child currently aged twenty months. CSD symptomatology usually begins during third trimester of pregnancy. Antenatal signs are polyhydramnios and diffuse intestinal dilation. Main differential diagnoses are intestinal obstructi...
Source: European Journal of Medical Genetics - July 2, 2019 Category: Genetics & Stem Cells Authors: Dimitrov G, Bamberger S, Navard C, Dreux S, Badens C, Bourgeois P, Buffat C, Hugot JP, Fabre A Tags: Eur J Med Genet Source Type: research

Secondary findings from next generation sequencing: Psychological and ethical issues. Family and patient perspectives.
In conclusion, individual experience and life context (circumstances) were decisive in participants' expectations and fears regarding access to SF. Additional longitudinal studies based on actual SF disclosure announcements are needed to establish future guidelines. PMID: 31265899 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - June 29, 2019 Category: Genetics & Stem Cells Authors: Houdayer F, Putois O, Babonneau ML, Chaumet H, Joly L, Juif C, Michon CC, Staraci S, Cretin E, Delanoue S, Charron P, Chassagne A, Edery P, Gautier E, Lapointe AS, Thauvin-Robinet C, Sanlaville D, Gargiulo M, Faivre L Tags: Eur J Med Genet Source Type: research

Controlled ovarian hyperstimulation (COH) parameters associated with euploidy rates in donor oocytes.
In this study, we investigated whether euploidy rates in the embryos created from donor oocytes are influenced by controlled ovarian hyperstimulation parameters used during assisted reproduction. Euploidy rates in egg donor cycles undergoing PGT-A (N = 423) were examined retrospectively for associations with donor age, gonadotropin doses (dose per day), the fraction of gonadotropin provided by hMG (F(hMG)), days of stimulation, estradiol per mature oocyte on day of trigger, number of mature oocytes retrieved, number of embryos biopsied, incidence of euploidy and physician of record. Differences in euploidy rates betwee...
Source: European Journal of Medical Genetics - June 25, 2019 Category: Genetics & Stem Cells Authors: McCulloh DH, Alikani M, Norian J, Kolb B, Arbones JM, Munné S Tags: Eur J Med Genet Source Type: research

Confirmation of a rare genetic leukoencephalopathy due to a novel Bi-allelic variant in RPIA.
We report on a subject with RPIA associated progressive leukoencephalopathy with elevated urine arabitol and ribitol levels and a novel missense variant c.770T > C p.(Ile257Thr) in exon 8 of RPIA. We also compare the phenotypes of all the four subjects. Our report confirms the phenotype and the genetic cause of this condition. PMID: 31247379 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - June 24, 2019 Category: Genetics & Stem Cells Authors: Kaur P, Wamelink MMC, van der Knaap MS, Girisha KM, Shukla A Tags: Eur J Med Genet Source Type: research

Ongoing issues with the management of children with Constitutional Mismatch Repair Deficiency syndrome.
We report the pedigree of a consanguineous family with four affected children. Although clinical and molecular tests confirm CMMRD, genetic testing revealed heterogeneous mutations. The index case developed severe toxicity from therapy for glioblastoma and T-cell leukemia and died from an infection while in complete remission. His sister developed a malignant brain tumor while undergoing surveillance for a low grade brain lesion and is still undergoing follow-up. This family illustrates the difficulties and opportunities with challenging diagnosis, surveillance and choice of therapy for children with CMMRD and the need for...
Source: European Journal of Medical Genetics - June 21, 2019 Category: Genetics & Stem Cells Authors: Farah RA, Maalouf F, Chahine NA, Farhat H, Campbell B, Zhukova N, Durno C, Aronson M, Hawkins C, Bouffet E, Tabori U Tags: Eur J Med Genet Source Type: research

Molecular genetic study of 59 Chinese Oculocutaneous albinism families.
In this study, compound heterozygous or homozygous pathogenic variants were found in 53 families, 4 families possessed only one heterozygous variant, and the pathogenic variants of 2 families remain undiscovered by using Sanger sequencing, whole exome sequencing and multiplex ligation-dependent probe amplification. We have identified a total of 55 variants including 21 novel variants in TYR, OCA2, SLC45A2, SLC24A5, and HPS1. The 21 novel variants include 11 missense changes, 4 nonsense changes, 2 splice site changes, 1 frameshift and 3 gross deletions. Forty-six variants including 14 novel variants were segregated with the...
Source: European Journal of Medical Genetics - June 20, 2019 Category: Genetics & Stem Cells Authors: Luo D, Linpeng S, Zeng L, Tan H, Li Z, Wu L Tags: Eur J Med Genet Source Type: research

Riluzole effectively treats psychotic symptoms and improves cognition in 22q11.2 deletion syndrome: A clinical case.
Abstract 22q11.2 deletion syndrome (22q11DS) is a genetic disorder caused by a hemizygous microdeletion on the long arm of chromosome 22 and is associated with a high risk for psychosis and cognitive impairment. One of the genes located in the deleted region of 22q11DS is Proline Dehydrogenase (PRODH) which is important for conversion of proline to glutamate. Glutamate is the primary excitatory neurotransmitter and is involved in the pathophysiology of psychosis as well as in cognition. Excessive concentrations are toxic. Possibly, neuroprotective drugs modulating glutamatergic neurotransmission could be effective...
Source: European Journal of Medical Genetics - June 20, 2019 Category: Genetics & Stem Cells Authors: Vingerhoets C, Tse DHY, van Amelsvoort T Tags: Eur J Med Genet Source Type: research

Endocervical trophoblast for interrogating the fetal genome and assessing pregnancy health at five weeks.
Abstract Prenatal testing for fetal genetic traits and risk of obstetrical complications is essential for maternal-fetal healthcare. The migration of extravillous trophoblast (EVT) cells from the placenta into the reproductive tract and accumulation in the cervix offers an exciting avenue for prenatal testing and monitoring placental function. These cells are obtained with a cervical cytobrush, a routine relatively safe clinical procedure during pregnancy, according to published studies and our own observations. Trophoblast retrieval and isolation from the cervix (TRIC) obtains hundreds of fetal cells with>90% ...
Source: European Journal of Medical Genetics - June 18, 2019 Category: Genetics & Stem Cells Authors: Kadam L, Jain C, Kohan-Ghadr HR, Krawetz SA, Drewlo S, Armant DR Tags: Eur J Med Genet Source Type: research

From phenotyping to genotyping - bioinformatics for the busy clinician.
Abstract Bioinformatics is a new scientific field. It applies computational and analysis tools to the capture, analyze and interpret large quantities of biological data. To understand genomic information, comparative analysis of data obtained is crucial. Primary physicians are dauntingly being implored to evaluate patients genetically, and analyze the results received. We depict online tools available for defining the clinical characteristics of a patient (phenotype), assisting in compiling them into a tentative genetic clinical diagnosis. The subsequent step is to then learn the patient's genotype and how to cura...
Source: European Journal of Medical Genetics - June 18, 2019 Category: Genetics & Stem Cells Authors: Reches A, Weiss K, Bazak L, Baris Feldman H, Maya I Tags: Eur J Med Genet Source Type: research

VPS51 biallelic variants cause microcephaly with brain malformations: A confirmatory report.
Abstract Whole exome sequencing undertaken in two siblings with delayed psychomotor development, absent speech, severe intellectual disability and postnatal microcephaly, with brain malformations consisting of cerebellar atrophy in the eldest affected and hypoplastic corpus callosum in the younger sister; revealed a homozygous intragenic deletion in VPS51, which encodes the vacuolar protein sorting-associated protein, one the four subunits of the Golgi-associated retrograde protein (GARP) and endosome-associated recycling protein (EARP) complexes that promotes the fusion of endosome-derived vesicles with the trans...
Source: European Journal of Medical Genetics - June 14, 2019 Category: Genetics & Stem Cells Authors: Uwineza A, Caberg JH, Hitayezu J, Wenric S, Mutesa L, Vial Y, Drunat S, Passemard S, Verloes A, El Ghouzzi V, Bours V Tags: Eur J Med Genet Source Type: research

Fabry disease caused by the GLA p.Phe113Leu (p.F113L) variant: Natural history in males.
CONCLUSIONS: Hemizygosity for the GLA Leu113 variant allele is associated with a late-onset form of FD, invariably presenting with severe cardiac involvement. Clinically relevant cerebrovascular and kidney involvement may also occur in some patients but the pathogenic relationship between the incomplete α-galactosidase deficiency and the risks of stroke and of chronic kidney disease is not straightforward. The observation that the Leu113 allele segregated within the same GLA microsatellite haplotype in both the Portuguese and Italian families suggests its inheritance from a common ancestor. PMID: 31200018 [PubMe...
Source: European Journal of Medical Genetics - June 11, 2019 Category: Genetics & Stem Cells Authors: Oliveira JP, Nowak A, Barbey F, Torres M, Nunes JP, Teixeira-E-Costa F, Carvalho F, Sampaio S, Tavares I, Pereira O, Soares AL, Carmona C, Cardoso MT, Jurca-Simina IE, Spada M, Ferreira S, Germain DP Tags: Eur J Med Genet Source Type: research

Why systematic literature reviews in fabry disease should include all published evidence.
Abstract Fabry disease is an X-linked inherited, progressive disorder of lipid metabolism resulting from the deficient activity of the enzyme α-galactosidase. Enzyme replacement therapy (ERT) with recombinant agalsidase, with intravenous infusions of either agalsidase beta or agalsidase alfa, is available and clinical experience now exceeds 15 years. There are very few randomised, placebo-controlled clinical trials evaluating the outcomes of enzyme replacement therapy (ERT). Data are often derived from observational, registry-based studies and case reports. Pooled analysis of data from different sources may ...
Source: European Journal of Medical Genetics - June 10, 2019 Category: Genetics & Stem Cells Authors: Elliott PM, Germain DP, Hilz MJ, Spada M, Wanner C, Falissard B Tags: Eur J Med Genet Source Type: research

Expanding the clinical history associated with syndromic Klippel-Feil: A unique case of comorbidity with medulloblastoma.
We present a 4-year-old male with KFS, who notably was also diagnosed with large-cell anaplastic medulloblastoma. We evaluated the genetic basis of co-occurring KFS and medulloblastoma and the role of MYO18B as related to medulloblastoma. Constitutional and somatic variant and copy number analyses were performed from DNA-based exome studies, along with RNA-sequencing of tumor tissue, to elucidate the genetic etiology of the co-existing disease states. We identified novel constitutional compound heterozygous frameshift variants (NM_032608.5: p.Leu2257SerfsTer16 and p.Arg2220SerfsTer74) each encoding a premature stop of tran...
Source: European Journal of Medical Genetics - June 10, 2019 Category: Genetics & Stem Cells Authors: Schieffer KM, Varga E, Miller KE, Agarwal V, Koboldt DC, Brennan P, Kelly B, Dave-Wala A, Pierson CR, Finlay JL, AbdelBaki MS, White P, Magrini V, Wilson RK, Mardis ER, Cottrell CE Tags: Eur J Med Genet Source Type: research

Novel BRPF1 mutation in a boy with intellectual disability, coloboma, facial nerve palsy and hypoplasia of the corpus callosum.
We report on an additional patient harboring a novel de novo nonsense mutation p.(Glu219*) in BRPF1. He presented with ID, bilateral iris colobomas, facial nerve palsy and severe hypoplasia of the corpus callosum. Our findings support previous findings of brain abnormalities in BRPF1-mutations and indicates coloboma and facial nerve palsy as possible additional features of IDDDFP syndrome. PMID: 31176769 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - June 6, 2019 Category: Genetics & Stem Cells Authors: Demeulenaere S, Beysen D, De Veuster I, Reyniers E, Kooy F, Meuwissen M Tags: Eur J Med Genet Source Type: research

A case of Woodhouse-Sakati syndrome with pituitary iron deposition, cardiac and intestinal anomalies, with a novel mutation in DCAF17.
We present a new case with pituitary iron deposition, cardiac and intestinal anomalies, with a novel mutation in DCAF17 gene. An 18-year-old female was admitted because of delayed puberty and amenorrhea. Hormonal evaluation revealed combined hyper-hypogonadotropic hypogonadism. GH and IGF-1 levels were low without short stature. ACTH levels were high and cortisol levels were supranormal with the lack of clinical findings of cortisol excess or deficiency. Pituitary MRI indicated paramagnetic substance deposition in gland. On follow-ups, non-autoimmune, insulinopenic diabetes mellitus and secondary hypothyroidism emerged. Wo...
Source: European Journal of Medical Genetics - May 29, 2019 Category: Genetics & Stem Cells Authors: Sendur SN, Oguz S, Utine GE, Dagdelen S, Oguz KK, Erbas T, Alikasifoglu M Tags: Eur J Med Genet Source Type: research

A novel frameshift variant in BHLHA9 underlies mesoaxial synostotic syndactyly associated with postaxial polydactyly.
Abstract Mesoaxial synostotic syndactyly (MSSD) with phalangeal reduction is an uncommon congenital limb abnormality characterized by central osseous synostosis at a metacarpal level, mesoaxial reduction of the fingers, and preaxial cutaneous syndactyly in toes. In rare cases, the disease is also associated with fifth finger clinodactyly and postaxial polydactyly. It has autosomal recessive inheritance pattern caused by homozygous variants in the gene BHLHA9 mapped at chromosome 17p13.3. In the present study, a consanguineous family of Pakistani origin segregating MSSD in autosomal recessive form was characterized...
Source: European Journal of Medical Genetics - May 29, 2019 Category: Genetics & Stem Cells Authors: Khan F, Arshad A, Majeed AI, Ullah A, Ahmad W Tags: Eur J Med Genet Source Type: research

Are we ready for genome editing in human embryos for clinical purposes?
Abstract Perhaps the two most significant pioneering biomedical discoveries with immediate clinical implications during the past forty years have been the advent of assisted reproductive technologies (ART) and the genetics revolution. ART, including in vitro fertilization (IVF), intracytoplasmic sperm injection and preimplantation genetic testing, has resulted in the birth of more than 8 million children, and the pioneer of IVF, Professor Bob Edwards, was awarded the 2010 Nobel Prize. The genetics revolution has resulted in our genomes being sequenced and many of the molecular mechanisms understood, and technologi...
Source: European Journal of Medical Genetics - May 28, 2019 Category: Genetics & Stem Cells Authors: Harper JC, Schatten G Tags: Eur J Med Genet Source Type: research

Deletion of exons 16-17b of CFTR is frequently identified in Korean patients with cystic fibrosis.
Abstract Cystic fibrosis (MIM #219700) is one of the most common autosomal recessively inherited diseases in Caucasians and is caused by pathogenic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. However, this disease is much less frequent in Asian populations. Here, we performed a clinical characterization of, and genetic analysis of CFTR in, Korean patients with cystic fibrosis. Six Korean patients from five families (two females and four males; median age, 12.5 years) were enrolled. Clinical data were assessed by retrospective review of medical records. The genetic variants of C...
Source: European Journal of Medical Genetics - May 25, 2019 Category: Genetics & Stem Cells Authors: Sohn YB, Ko JM, Jang JY, Seong MW, Park SS, Suh DI, Ko JS, Shin CH Tags: Eur J Med Genet Source Type: research

Theory and practice of preimplantation genetic screening (PGS).
CONCLUSION: PGS may be beneficial if used with strict indications, taking into account stochastics and the will of the patient. The task of the physician, similar to counselling in prenatal medicine, is as follows: present all methods of investigation and respect the will of the patient. PMID: 31136844 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - May 25, 2019 Category: Genetics & Stem Cells Authors: Schmutzler AG Tags: Eur J Med Genet Source Type: research

Coexistence of schwannomatosis and glioblastoma in two families.
We report here two families in which segregate both multiple schwannomas and GB. In the first family, the proband received a diagnosis with of schwannomatosis after a surgery for a lumbar schwannoma at age 43, molecularly confirmed by identification of a germline heterozygous mutation in LZTR1. Her father, having unremarkable medical history deceased from an apparently isolated GB at age 59. In the second family, LZTR1-related schwannomatosis was diagnosed in the index case at age 70 after multiple schwannomas surgeries. Her elder sister had no neurological medical history before occurrence of a lethal GB at age 78. Molecu...
Source: European Journal of Medical Genetics - May 22, 2019 Category: Genetics & Stem Cells Authors: Deiller C, Van-Gils J, Zordan C, Tinat J, Loiseau H, Fabre T, Delleci C, Cohen J, Vidaud M, Parfait B, Goizet C Tags: Eur J Med Genet Source Type: research

An acquired or heritable connective tissue disorder? A review of hypermobile Ehlers Danlos Syndrome.
Abstract Hypermobile Ehlers Danlos Syndrome (hEDS) is a multifaceted disorder that is difficult to diagnose and manage primarily due to the unknown causes. Research on hEDS continues to evolve but tangible progress will be realized when the growing body of evidence compliments clinical practice. This critical review of the literature aims to stimulate lateral thinking about the pathogenesis, diagnosis and management of hEDS. The current international classification of Ehlers Danlos Syndrome introduced stricter diagnostic criteria for hEDS, which bore a blanket category (hypermobility spectrum disorders) for condit...
Source: European Journal of Medical Genetics - May 15, 2019 Category: Genetics & Stem Cells Authors: Martin A Tags: Eur J Med Genet Source Type: research

Contribution of GRB10 to the prenatal phenotype in Silver-Russell syndrome? Lessons from 7p12 copy number variations.
Abstract The growth factor binding protein 10 (GRB10) has been suggested as a candidate gene for Silver-Russell syndrome because of its localization in 7p12, its imprinting status, data from mice models and its putative role in growth. Based on a new patient with normal growth carrying a GRB10 deletion affecting the paternal allele and data from the literature, we conclude that the heterogeneous clinical findings in patients with copy number variations (CNVs) of GRB10 gene depend on the size and the gene content of the CNV. However, evidence from mouse and human cases indicate a growth suppressing role of GRB10 in...
Source: European Journal of Medical Genetics - May 14, 2019 Category: Genetics & Stem Cells Authors: Eggermann T, Begemann M, Kurth I, Elbracht M Tags: Eur J Med Genet Source Type: research

Update on the use of exome sequencing in the diagnosis of fetal abnormalities.
Abstract Unexpected fetal abnormalities detected through ultrasound scanning in pregnancy may have a monogenic aetiology but are difficult to diagnose. Next generation sequencing now enables us to sequence fetal exomes, providing increased resolution and broader diagnostic capability compared to traditional cytogenetic prenatal tests, improving the yield and accuracy of diagnoses and allowing better counselling for expectant parents. Here we review published studies of exome sequencing (ES) for prenatal diagnosis over the last 5 years and address important questions for its clinical implementation, including clini...
Source: European Journal of Medical Genetics - May 11, 2019 Category: Genetics & Stem Cells Authors: Ferretti L, Mellis R, Chitty LS Tags: Eur J Med Genet Source Type: research

Personal genomic screening: How best to facilitate preparedness of future clients.
Abstract Personal genome screening (PGenS) is increasingly being offered as a screen for future health management, and to identify carrier status pertinent to reproductive decision-making. The aim of this study was therefore to explore the experience of individuals who undertook PGenS through the 2014 Sydney "Understand Your Genome (UYG)" event and a 2015 offer of PGenS by Australian biotechnology company Life Letters (LL). Eligible individuals were invited to participate by their clinical geneticist (UYG), or email from Director of LL. Semi-structured telephone interviews with 17 individuals were audio-...
Source: European Journal of Medical Genetics - May 11, 2019 Category: Genetics & Stem Cells Authors: Fleming J, Terrill B, Dziadek M, Kirk EP, Roscioli T, Barlow-Stewart K Tags: Eur J Med Genet Source Type: research

The demise of preimplantation genetic testing for aneuploidy (PGT-A) in Hungary and its effect on patient care.
acute;, Csenki M, Vereczkey A Abstract Preimplantation genetic testing for aneuploidy (PGT-A) is a suitable technique to identify euploid embryos, which have the highest potential to implant, thus increase the chance of a healthy live birth. The main indications of PGT-A are advanced maternal age, repeated implantation failure, repeated miscarriages and severe male infertility. Several studies have already proven that testing embryos for genetic abnormalities in the above cases results in higher implantation rate and reduced number of pregnancy loss. In spite of these - due to a legislative change in Hungary in 20...
Source: European Journal of Medical Genetics - May 10, 2019 Category: Genetics & Stem Cells Authors: Varga K, Tóth N, Bogár ÉB, Csontos L, Szabó K, Debreceni D, Margittai É, Csenki M, Vereczkey A Tags: Eur J Med Genet Source Type: research

Clinical spectrum of congenital tibial hemimelia in 35 limbs of 24 patients: A single center observational study from India.
CONCLUSION: Reports of more TH cases will provide input to researchers to consider comprehensive rehabilitation for enhancing indoor and community ambulation. PMID: 31078790 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - May 9, 2019 Category: Genetics & Stem Cells Authors: Kumar Sahoo P, Sahu MM, Prasad Das S Tags: Eur J Med Genet Source Type: research

Screening of a large cohort of blepharophimosis, ptosis, and epicanthus inversus syndrome patients reveals a very strong paternal inheritance bias and a wide spectrum of novel FOXL2 mutations.
This study demonstrates the importance of cascade screening and provides new information on inheritance and parental mosaicism in BPES which will aid genetic counselling and accurate risk management. PMID: 31077882 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - May 8, 2019 Category: Genetics & Stem Cells Authors: Bunyan DJ, Thomas NS Tags: Eur J Med Genet Source Type: research

Homozygous deletion of the entire AAAS gene in a triple A syndrome patient.
Abstract Triple A syndrome, a multisystemic autosomal recessive disease, is characterized by the clinical triad of adrenal insufficiency, alacrima and achalasia in combination with progressive neurological impairments. The disorder is caused by homozygous or compound heterozygous mutations in the AAAS gene. Here we present the clinical and molecular data of a ten year old patient with triple A syndrome. Array-CGH analysis confirmed the PCR-based assumption of a homozygous deletion of the entire AAAS gene in the patient and a heterozygous deletion in both parents. We demonstrate that the patient carries a 15 kb d...
Source: European Journal of Medical Genetics - May 6, 2019 Category: Genetics & Stem Cells Authors: Koehler K, Hackmann K, Landgraf D, Schubert T, Shakiba M, Kariminejad A, Huebner A Tags: Eur J Med Genet Source Type: research

A novel pathogenic variant in TNPO3 in a Hungarian family with limb-girdle muscular dystrophy 1F.
egh B Abstract Limb-girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous muscular diseases that predominantly affect the proximal muscles. Pathogenic variants in TNPO3 have been associated with a rare, autosomal dominant limb-girdle muscular dystrophy 1F (LGMD1F) in a large Italian-Spanish family and an isolated LGMD1F case. Here we present two individuals from a Hungarian family with an early-onset, slowly progressive muscular dystrophy. Both the female proband and her affected son had delayed early motor milestones including first walking at 14 months and 18 months, respectively. Both pre...
Source: European Journal of Medical Genetics - May 6, 2019 Category: Genetics & Stem Cells Authors: Pál E, Zima J, Hadzsiev K, Ito YA, Hartley T, Care4Rare Canada Consortium, Boycott KM, Melegh B Tags: Eur J Med Genet Source Type: research

Ophthalmo-acromelic syndrome in an infant.
Ouml;, Utine GE Abstract Ophthalmo-acromelic syndrome is a rare autosomal recessive disorder characterised by ocular and skeletal abnormalities. Ocular findings present as a wide spectrum, ranging from mild microphthalmia to true anophthalmia. Short 5th finger, synostosis of 4th and 5th metacarpals, and oligodactyly in feet are frequent limb malformations. Homozygous variants in the SMOC1 gene (SPARC-related modular calcium-binding protein 1 gene) were identified as causative for the syndrome. A 9-month-old female patient is presented herein, who was diagnosed with ophthalmo-acromelic syndrome and had a homozygous...
Source: European Journal of Medical Genetics - May 5, 2019 Category: Genetics & Stem Cells Authors: Ürel-Demir G, Taşkıran EZ, Akgün-Doğan Ö, Şimşek-Kiper PÖ, Utine GE Tags: Eur J Med Genet Source Type: research

Chemical screens in a zebrafish model of CHARGE syndrome identifies small molecules that ameliorates disease like phenotypes in embryo.
Abstract CHARGE syndrome is an autosomal dominant congenital disorder caused primarily by mutations in the CHD7 gene. Using a small molecule screen in a zebrafish model of CHARGE syndrome, we identified 4 compounds that rescue embryos from disease-like phenotypes. Our screen yielded DAPT, a Notch signaling inhibitor that could ameliorate the craniofacial, cranial neuronal and myelination defects in chd7 morphant zebrafish embryos. We discovered that Procainamide, an inhibitor of DNA methyltransferase 1, was able to recover the pattern of expression of isl2a, a cranial neuronal marker while also reducing the effect...
Source: European Journal of Medical Genetics - April 30, 2019 Category: Genetics & Stem Cells Authors: Asad Z, Sachidanandan C Tags: Eur J Med Genet Source Type: research