Dystonia as initial presentation of compound heterozygous GBA2 mutations: Expanding the phenotypic spectrum of SPG46.
We report clinical, genetic and brain imaging findings in two siblings with hereditary spastic paraparesis. One sister presented with juvenile-onset leg spasticity and progressed to spastic tetraparesis, cervical and jaw opening dystonia, pseudobulbar symptoms and dementia. The other sister initially developed cervical dystonia in adulthood followed by gait spasticity and cognitive decline in the disease course. Molecular genetic testing revealed novel compound heterozygous variants in GBA2 in both sisters. The initial presentation with cervical dystonia and the differing clinical disease progression expand the clinical ph...
Source: European Journal of Medical Genetics - June 23, 2020 Category: Genetics & Stem Cells Authors: Kloth K, Cozma C, Bester M, Gerloff C, Biskup S, Zittel S Tags: Eur J Med Genet Source Type: research

Enteric anendocrinosis attributable to a novel Neurogenin-3 variant.
Abstract Congenital diarrhea and enteropathies (CODEs) are a group of monogenic disorders that often present with severe diarrhea in the first weeks of life. Enteric anendocrinosis (EA), an extremely rare cause of CODE, is characterized by a marked reduction of intestinal enteroendocrine cells (EC). EA is associated with recessively inherited variants in Neurogenin-3 (NEUROG3) gene. Here we investigate a case of a male infant who presented with mysterious severe malabsorptive diarrhea since birth. Thorough clinical assessments and laboratory tests were successful to exclude the majority of differential diagnosis c...
Source: European Journal of Medical Genetics - June 20, 2020 Category: Genetics & Stem Cells Authors: Azab B, Dardas Z, Rabab'h O, Srour L, Telfah H, Hatmal MM, Mustafa L, Rashdan L, Altamimi E Tags: Eur J Med Genet Source Type: research

Answer to Letter to the Editor regarding the article "Striking phenotypic overlap between Nicolaides-Baraitser and Coffin-Siris syndromes in monozygotic twins with ARID1B intragenic deletion".
Answer to Letter to the Editor regarding the article "Striking phenotypic overlap between Nicolaides-Baraitser and Coffin-Siris syndromes in monozygotic twins with ARID1B intragenic deletion". Eur J Med Genet. 2020 Jun 20;:103993 Authors: Pascolini G, Valiante M, Bottillo I, Laino L, Ferraris A, Grammatico P, Fleischer N PMID: 32574611 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - June 20, 2020 Category: Genetics & Stem Cells Authors: Pascolini G, Valiante M, Bottillo I, Laino L, Ferraris A, Grammatico P, Fleischer N Tags: Eur J Med Genet Source Type: research

Natural human chimeras: A review.
Abstract The term chimera has been borrowed from Greek mythology and has a long history of use in biology and genetics. A chimera is an organism whose cells are derived from two or more zygotes. Recipients of tissue and organ transplants are artificial chimeras. This review concerns natural human chimeras. The first human chimera was reported in 1953. Natural chimeras can arise in various ways. Fetal and maternal cells can cross the placental barrier so that both mother and child may become microchimeras. Two zygotes can fuse together during an early embryonic stage to form a fusion chimera. Most chimeras remain u...
Source: European Journal of Medical Genetics - June 18, 2020 Category: Genetics & Stem Cells Authors: Madan K Tags: Eur J Med Genet Source Type: research

Phenotype description in KIF5C gene hot-spot mutations responsible for malformations of cortical development (MCD).
We report the natural history of a sixteen years old patient identified carrier of a KIF5C gene mutation who developed infantile epilepsy. We then gather phenotype description and molecular results of all reported patients so far in order to better define this entity. PMID: 32562872 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - June 17, 2020 Category: Genetics & Stem Cells Authors: Duquesne S, Nassogne MC, Clapuyt P, Stouffs K, Sznajer Y Tags: Eur J Med Genet Source Type: research

Genetics of developmental dysplasia of the hip.
Abstract In the last decade, the advances in the molecular analyses and sequencing techniques allowed researchers to study developmental dysplasia of the hip (DDH) more thoroughly. Certain chromosomes, genes, loci and polymorphisms are being associated with variable severity of this disorder. The wide range of signs and symptoms is dependent either on isolated or systemic manifestation. Phenotypes of isolated cases range from only a mild ligamental laxity, through subluxation, to a complete dislocation of the femoral head. Systemic manifestation is connected to various forms of skeletal dysplasia and other malform...
Source: European Journal of Medical Genetics - June 12, 2020 Category: Genetics & Stem Cells Authors: Harsanyi S, Zamborsky R, Kokavec M, Danisovic L Tags: Eur J Med Genet Source Type: research

Free, online videos for distance learning in medical genetics.
PMID: 32540377 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - June 12, 2020 Category: Genetics & Stem Cells Authors: Maggipinto S, Chen A, Huynh D, Heutlinger O, Eberenz K, Mallick S, Marshall T, Desai R, Wolbrink TA, Boone PM Tags: Eur J Med Genet Source Type: research

Ligase IV syndrome can present with microcephaly and radial ray anomalies similar to Fanconi anaemia plus fatal kidney malformations.
Abstract Ligase IV (LIG4) syndrome is a rare disorder of DNA damage repair caused by biallelic, pathogenic variants in LIG4. This is a phenotypically heterogeneous condition with clinical presentation varying from lymphoreticular malignancies in developmentally normal individuals to significant microcephaly, primordial dwarfism, radiation hypersensitivity, severe combined immunodeficiency and early mortality. Renal defects have only rarely been described as part of the ligase IV disease spectrum. We identified a consanguineous family where three siblings presenting with antenatal growth retardation, microcephaly, ...
Source: European Journal of Medical Genetics - June 11, 2020 Category: Genetics & Stem Cells Authors: Madhu R, Beaman GM, Chandler KE, O'Sullivan J, Urquhart JE, Khan N, Martindale E, Briggs TA, Clayton-Smith J, Higgs J, Batra G, Kerr B, Woolf AS, Newman WG Tags: Eur J Med Genet Source Type: research

Double heterozygous variants in FBN1 and FBN2 in a Thai woman with Marfan and Beals syndromes.
In this study, we identified the fourth patient with both MFS and BS, carrying mutations in both FBN1 and FBN2. PMID: 32534992 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - June 11, 2020 Category: Genetics & Stem Cells Authors: Phokaew C, Sittiwangkul R, Suphapeetiporn K, Shotelersuk V Tags: Eur J Med Genet Source Type: research

A missense variant, p.(Ile269Asn), in MC4R as a secondary finding in a child with BCL11A-related intellectual disability.
We describe a three year old female who underwent clinical exome sequencing and was diagnosed with BCL11A-related intellectual disability/Dias-Logan syndrome due to a de novo, heterozygous variant in the BCL11A gene, NM_018014.3:c.148C  >  T; p.(Gln50*). A missense variant in MC4R, NM_005912.3:c.806T  >  A; p.(Ile269Asn), was also reported as a secondary finding. In her family, her father, paternal aunt, and paternal uncle were all reported to have height and weight measurements suggestive of Class 3 obesity with BMI>40 kg/m2. The MC4R gene is not currently listed among those recommende...
Source: European Journal of Medical Genetics - June 10, 2020 Category: Genetics & Stem Cells Authors: Beleford DT, Van Ziffle J, Hodoglugil U, Slavotinek AM Tags: Eur J Med Genet Source Type: research

Rare homozygous nonsense variant in AIMP1 causing Early Onset Epileptic Encephalopathy with Burst Suppression (EOEE-BS).
This report expands the genetic landscape of EOEE-BS. This is the first case of this specific variant in which Epidiolex was administered, which along with Ketogenic diet aided in controlling patient's super refractory status epilepticus. PMID: 32531460 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - June 9, 2020 Category: Genetics & Stem Cells Authors: Gupta S, Schwab M, Valdez-Gonzalez K, Segal E Tags: Eur J Med Genet Source Type: research

Focal segmental glomerulosclerosis and mild intellectual disability in a patient with a novel de novo truncating TRIM8 mutation.
Abstract Mutations in the TRIM8 gene have been described in patients with severe developmental delay, intellectual disability and epilepsy. Only six patients have been described to date. All the previous mutations were truncating variants clustered in the C-terminus of the protein. A previous patient with TRIM8-related epileptic encephalopathy was reported to have nephrotic syndrome. Here we describe the clinical, radiological and histological features of an 8-year-old male patient with a TRIM8 mutation who, in contrast to previous patients, had only mild intellectual disability and well-controlled epilepsy. The p...
Source: European Journal of Medical Genetics - June 9, 2020 Category: Genetics & Stem Cells Authors: McClatchey MA, du Toit ZD, Vaughan R, Whatley SD, Martins S, Hegde S, Naude JTW, Thomas DH, Griffiths DF, Research Consortium GE, Clarke AJ, Fry AE Tags: Eur J Med Genet Source Type: research

New insights on the clinical variability of FKBP10 mutations.
Abstract To date 45 autosomal recessive disease-causing variants are reported in the FKBP10 gene. Those variant were found to be associated with Osteogenesis Imperfecta (OI) for which the hallmark phenotype is bone fractuers or Bruck Syndrome (BS) where bone fractures are accompanied with contractures. In addition, a specific homozygous FKBP10 mutation (p.Tyr293del) has been described in Yup'ik Inuit population to cause Kuskokwim syndrome (KS) in which contractures without fractures are observed. Here we present an extended Palestinian family with 10 affected individuals harboring a novel homozygous splice site mu...
Source: European Journal of Medical Genetics - June 9, 2020 Category: Genetics & Stem Cells Authors: Essawi OH, Tapaneeyaphan P, Symoens S, Gistelinck C C, Malfait F, Eyre DR, Essawi T, Callewaert B, Coucke PJ Tags: Eur J Med Genet Source Type: research

An intronic splice site alteration in combination with a large deletion affecting VPS13B (COH1) causes Cohen syndrome.
LM Abstract Cohen syndrome (CS) is a rare, autosomal recessive disorder characterized by intellectual disability, postnatal microcephaly, facial abnormalities, abnormal truncal fat distribution, myopia, and pigmentary retinopathy. It is often considered an underdiagnosed condition, especially in children with developmental delay and intellectual disability. Here we report on four individuals from a large Jordanian family clinically diagnosed with CS. Using Trio Exome Sequencing (Trio-WES) and MLPA analyses we identified a maternally inherited novel intronic nucleotide substitution c.3446-23T > G leading to...
Source: European Journal of Medical Genetics - June 4, 2020 Category: Genetics & Stem Cells Authors: Boschann F, Fischer-Zirnsak B, Wienker TF, Holtgrewe M, Seelow D, Eichhorn B, Döhnert S, Fahsold R, Horn D, Graul-Neumann LM Tags: Eur J Med Genet Source Type: research

Impact of direct-to-consumer genetic testing on Australian clinical genetics services.
Abstract The increasing popularity of direct-to-consumer genetic testing (DTCGT) is thought to be creating a burden on clinical genetic services worldwide. However, no Australian studies have collected recent evidence regarding this impact. We surveyed Australian clinical genetics services about DTCGT-related referrals over the past 10 years. Eleven publicly-funded services reported over 100 DTCGT-related referrals. Most (83%) involved general practitioners seeking interpretation of DTCGT results. More than 30% involved imputed risk estimates from third-party software tools. Services reported low validation rates for DTCGT results (
Source: European Journal of Medical Genetics - June 2, 2020 Category: Genetics & Stem Cells Authors: Millward M, Tiller J, Bogwitz M, Kincaid H, Taylor S, Trainer AH, Lacaze P Tags: Eur J Med Genet Source Type: research

Unique skeletal manifestations in patients with Primrose syndrome.
We describe five unrelated patients with Primrose syndrome and distinct skeletal features including multiple Wormian bones, platybasia, bitemporal bossing, bathrocephaly, slender bones, epiphyseal and spondylar dysplasia. The radiological abnormalities of the skull and the epiphyseal dysplasia were the most consistent findings. This novel constellation of skeletal features expands the phenotypic spectrum of the disorder. PMID: 32473227 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - May 27, 2020 Category: Genetics & Stem Cells Authors: Arora V, Leon E, Diaz J, Hove HB, Carvalho DR, Kurosawa K, Nishimura N, Nishimura G, Saxena R, Ferreira C, Puri RD, Verma IC Tags: Eur J Med Genet Source Type: research

Case of 15q26-qter deletion associated with a Prader-Willi phenotype.
ho AF Abstract Prader-Willi syndrome (PWS) is one of the common neurogenetic disorders associated with intellectual disability. PWS involves a complex inheritance pattern and is caused by an absence of gene expression on the paternally inherited 15q11.2-q13 region, either due to deletion, maternal uniparental disomy or imprinting defect. The syndrome is characterized principally by severe neonatal hypotonia, a weak suck in infancy that is later followed by hyperphagia and obesity, developmental delay, intellectual disability and short stature. In the case of the chromosome 15q26-qter deletion syndrome or Drayer's ...
Source: European Journal of Medical Genetics - May 27, 2020 Category: Genetics & Stem Cells Authors: Fernandes Dos Santos J, Acosta AX, GayerScheibler G, Leite Pitanga PM, Alves ES, Castro Meira JG, Zanardo ÉA, Kulikowski LD, Leite Ferreira de Lima RL, Lacerda de Carvalho AF Tags: Eur J Med Genet Source Type: research

A novel homozygous missense variant in MATN3 causes spondylo-epimetaphyseal dysplasia Matrilin 3 type in a consanguineous family.
Abstract Spondylo-epimetaphyseal dysplasia Matrilin 3 type (SEMD) is a rare autosomal recessive skeletal dysplasia characterized by short stature, abnormalities in the vertebral bodies and long bones, especially the lower limbs. We enrolled a consanguineous family from Pakistan in which multiple siblings suffered from severe skeletal dysplasia. The six affected subjects ranged in heights from 100 to 136 cm (∼-6 standard deviation). Lower limb abnormalities with variable varus and valgus deformities and joint dysplasia were predominant features of the clinical presentation. Whole exome sequencing (WES) follow...
Source: European Journal of Medical Genetics - May 26, 2020 Category: Genetics & Stem Cells Authors: Yasin S, Mustafa S, Ayesha A, Latif M, Hassan M, Faisal M, Makitie O, Iqbal F, Naz S Tags: Eur J Med Genet Source Type: research

Cowden syndrome complicated by schizophrenia: A first clinical report.
Abstract Patients with Cowden syndrome exhibit mucocutaneous lesions, hamartomatous polyposis of the gastrointestinal tract, and macrocephaly, often complicated by malignant tumors, such as breast, thyroid, and uterine cancers. Autism spectrum and epilepsy have been known as neuropsychiatric symptoms associated with Cowden syndrome; however, to the best of our knowledge, there is no report on cases complicated by schizophrenia. Here, we report a first case of Cowden syndrome complicated by schizophrenia. A 49-year-old Japanese woman started experiencing auditory hallucinations in her teens. She had left breast can...
Source: European Journal of Medical Genetics - May 24, 2020 Category: Genetics & Stem Cells Authors: Kobayashi Y, Takeda T, Kunitomi H, Ueki A, Misu K, Kowashi A, Takahashi T, Anko M, Watanabe K, Masuda K, Uchida T, Tominaga E, Banno K, Kosaki K, Aoki D Tags: Eur J Med Genet Source Type: research

Long-term follow-up and novel genotype-phenotype analysis of monozygotic twins with ATP1A3 mutation in Alternating Hemiplegia of Childhood-2.
Abstract Alternating Hemiplegia of Childhood (AHC) is a rare disorder characterized by frequent, transient attacks of hemiplegia involving either side of the body or both in association to several other disturbances including dystonic spells, abnormal ocular movements, autonomic manifestations, epileptic seizures and cognitive impairment. The clinical manifestations usually start before the age of 18 months. Two forms of the disorder known as AHC-1 (MIM#104290) and AHC-2 (MIM#614820) depends on mutations in ATP1A2 and ATP1A3 genes respectively, with over 75% of AHC caused by a mutation in the ATP1A3 gene. Herewith...
Source: European Journal of Medical Genetics - May 23, 2020 Category: Genetics & Stem Cells Authors: Pavone P, Pappalardo XG, Incorpora G, Falsaperla R, Marino SD, Corsello G, Parano E, Ruggieri M Tags: Eur J Med Genet Source Type: research

Defining the TRPM3 related spectrum: Possible ocular and joints defects, and inconstant epilepsy.
We report a novel patient with the same recurrent de novo missense of TRPM3 found in seven of these eight cases, p.(Val837Met), but with a slightly different phenotype. PMID: 32439617 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - May 18, 2020 Category: Genetics & Stem Cells Authors: Agathe JS, Van-Gils J, Lasseaux E, Arveiler B, Lacombe D, Pfirrmann C, Raclet V, Gaston L, Plaisant C, Aupy J, Trimouille A Tags: Eur J Med Genet Source Type: research

Exome sequencing revealed a novel homozygous METTL23 gene mutation leading to familial mild intellectual disability with dysmorphic features.
CONCLUSION: Hereby, we highlight the similarity of the dysmorphic traits and the characteristic facial features in patients with METTL23-related intellectual disability, suggesting the consideration of a distinct clinical entity associating mild intellectual deficiency with specific facial dysmorphy for an efficient diagnosis orientation and a better phenotype-genotype correlation in intellectual disability disorders. PMID: 32439618 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - May 18, 2020 Category: Genetics & Stem Cells Authors: Smaili W, Elalaoui SC, Zrhidri A, Raymond L, Egéa G, Taoudi M, Mouatassim SEL, Sefiani A, Lyahyai J Tags: Eur J Med Genet Source Type: research

Prenatal diagnosis of 2q13 duplications: The crucial role of the family survey in genetic counseling on novel copy number variations.
Abstract In recent years, the introduction of novel genome analysis technologies (such as array comparative genomic hybridization) has enabled the prenatal diagnosis of various recurrent copy number variations (CNVs). Some of these CNVs have been linked to a greater susceptibility of developmental and neuropsychiatric disorders; for example, recurrent duplication at the 2q13 locus is associated with developmental delay, dysmorphism and intellectual disability. However, this CNV has low penetrance and variable clinical expressivity. It also can be observed in healthy controls and can be transmitted by unaffected pa...
Source: European Journal of Medical Genetics - May 18, 2020 Category: Genetics & Stem Cells Authors: Bellil H, Molina-Gomes D, Quibel T, Roy S, Dard R, Vialard F, Herve B Tags: Eur J Med Genet Source Type: research

Acute liver failure in a male patient with NGLY1-congenital disorder of deglycosylation.
We report a five-year-old male patient who presented a severe episode of acute liver failure (ALF). Exome sequencing identified compound heterozygous pathogenic/likely pathogenic variants in the NGLY1 gene: NM_018297.3:c.1891del, p.(Gln631Serfs*7) in exon 12 and NM_018297.3:c.531dup, p.(Asn178Glnfs*9) in exon 4. Serology for the most frequent viral hepatitis infections, autoimmune panel, and investigations for metabolic or toxic causes were also normal or negative. Hepatic disease resolved favorably after 46 days. Liver function tests and elastography remains normal after a 2-year follow-up. This is the first report of a r...
Source: European Journal of Medical Genetics - May 15, 2020 Category: Genetics & Stem Cells Authors: Rios-Flores IM, Bonal-Pérez MÁ, Castellanos-González A, Velez-Gómez E, Bertoli-Avella AM, Bobadilla-Morales L, Peña-Padilla C, Appendini-Andrade V, Corona-Rivera A, Romero-Valenzuela I, Corona-Rivera JR Tags: Eur J Med Genet Source Type: research

Various phenotypes of disease associated with mutated DGKE gene.
We present a child with steroid-resistant nephrotic syndrome and a confirmed homozygous c.966G > A, p.Trp322Ter pathogenic variant in DGKE. This variant was also found in compound with a novel DGKE heterozygous deletion c.171delG, p.Ser58Alafs*111 in a patient from our paediatric cohort with atypical haemolytic uraemic syndrome. Both cases presented with hypertension, nephrotic proteinuria and severe acute kidney injury followed by renal recovery; however, their renal histology was different. In this paper, we deal with the clinical course of children with disrupted DGKE, including the steroid-resistant nephrotic sy...
Source: European Journal of Medical Genetics - May 12, 2020 Category: Genetics & Stem Cells Authors: Bezdíčka M, Pavlíček P, Bláhová K, Háček J, Zieg J Tags: Eur J Med Genet Source Type: research

Biallelic variants in four genes underlying recessive osteogenesis imperfecta.
In conclusion, our findings provided additional evidence of involvement of homozygous sequence variants in the SP7, SERPINF1, SPARC and WNT1 genes causing severe OI. It also highlights the importance of extensive genetic investigations to search for the culprit gene in each case of skeletal deformity. PMID: 32413570 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - May 12, 2020 Category: Genetics & Stem Cells Authors: Hayat A, Hussain S, Bilal M, Kausar M, Almuzzaini B, Abbas S, Tanveer A, Khan A, Siddiqi S, Foo JN, Ahmad F, Khan F, Khan B, Anees M, Mäkitie O, Alfadhel M, Ahmad W, Umair M Tags: Eur J Med Genet Source Type: research

Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) initially diagnosed as ALG6-CDG: Functional evidence for benignity of the ALG6 c.391T > C (p.Tyr131His) variant and further expanding the BBSOAS phenotype.
In this report, we extend the phenotype of BBSOAS with ataxia and protein-losing enteropathy. This case is illustrative of the utility of whole exome sequencing in the diagnostic odyssey, and the potential pitfalls of relying on focused genetic testing results for diagnosis of conditions with complex overlapping phenotypes. PMID: 32407885 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - May 11, 2020 Category: Genetics & Stem Cells Authors: Starosta RT, Tarnowski J, Pinto E Vairo F, Raymond K, Preston G, Morava E Tags: Eur J Med Genet Source Type: research

Screening of a large PAX6 cohort identified many novel variants and emphasises the importance of the paired and homeobox domains.
Abstract Pathogenic variants within PAX6 are most often associated with aniridia, but have been linked with other phenotypes such as nystagmus, cataracts and foveal hypoplasia. Data are presented from a large cohort of 434 probands referred for PAX6 diagnostic testing. This analysis identified a wide range of pathogenic variants (n = 145) in 254 probands (including 61 novel variants). Excluding missense variants predicted to affect splicing, all 29 of the remaining missense variants were located within the paired (n = 27) or homeobox (n = 2) domains of the PAX6 protein, providing further evidence that ...
Source: European Journal of Medical Genetics - April 30, 2020 Category: Genetics & Stem Cells Authors: Cross E, Duncan-Flavell PJ, Howarth RJ, Crooks RO, Thomas NS, Bunyan DJ Tags: Eur J Med Genet Source Type: research

First reported case of Steel syndrome in the European population: A novel homozygous mutation in COL27A1 and review of the literature.
Abstract Steel syndrome is an autosomal recessive disorder that primarily affects the skeletal system causing a variety of manifestations. Sixteen individuals with Steel syndrome, mainly Puerto Ricans (11/16), were previously reported to carry bi-allelic mutations in the COL27A1 gene. Here, we present the first patient with Steel syndrome in Europe and the sixth non-Puerto Rican carrying a novel homozygous mutation in COL27A1. The patient is a 4-year-old boy born to non-consanguineous healthy parents, with dysmorphic facial features, absent hip ossification centres, external rotation of both feet, relatively short...
Source: European Journal of Medical Genetics - April 30, 2020 Category: Genetics & Stem Cells Authors: Evie K, Athina T, Nayia N, Angelos A, Ioannis P, Elisavet E, Violetta CA, Carolina S, George TA Tags: Eur J Med Genet Source Type: research

Pontocerebellar hypoplasia type 11: Does the genetic defect determine timing of cerebellar pathology?
I, Haack TB Abstract Pontocerebellar hypoplasia (PCH) comprises a clinically and genetically heterogeneous group of disorders characterized by hypoplasia and degeneration of the cerebellum and ventral pons. To date at least 18 different clinical subtypes of PCH associated with pathogenic variants in 19 different genes have been described. Only recently, bi-allelic variants in TBC1D23 have been reported as the underlying molecular defect in seven index cases with a suspected non-degenerative form of PCH, PCH type 11 (PCH11). We used exome sequencing to investigate an individual with global developmental delay, atax...
Source: European Journal of Medical Genetics - April 28, 2020 Category: Genetics & Stem Cells Authors: Laugwitz L, Buchert R, Groeschel S, Riess A, Grimmel M, Beck-Wödl S, Sturm M, Gohla G, Döbler-Neumann M, Krägeloh-Mann I, Haack TB Tags: Eur J Med Genet Source Type: research

Clinical and molecular characterization of pediatric mitochondrial disorders in south of China.
Abstract Mitochondrial disorders (MDs) are genetic ailments affecting all age groups. Epidemiological data and frequencies of gene mutations in pediatric patients in China are scarce. This retrospective study assessed 101 patients with suspected MDs treated at the Neurology Department of Children's Hospital, Fudan University, in 2011-2017. Mitochondrial (mtDNA) and nuclear (nDNA) samples were assessed by long-range polymerase chain reaction (PCR)-based whole mtDNA sequencing and whole exome sequencing (WES) for identifying pathogenic mutations. Muscle samples underwent various staining protocols and immunofluoresc...
Source: European Journal of Medical Genetics - April 26, 2020 Category: Genetics & Stem Cells Authors: Hu C, Li X, Zhao L, Shi Y, Wu B, Zhou S, Wang Y Tags: Eur J Med Genet Source Type: research

Congenital hyperinsulinism due to mutations in HNF1A.
We describe two cases of congenital hyperinsulinism in association with dominantly inherited variants in HNF1A. They presented in the early neonatal period with unequivocal biochemical evidence of congenital hyperinsulinism and persistence into childhood with ongoing need for medical therapy. Both cases inherited HNF1A variants from a parent with a diabetes phenotype consistent with MODY, without obesity, insulin resistance or other metabolic syndrome features. In the first case, a paternally inherited novel c.-230_-101del variant was found that deletes the minimal promoter region presumably required for HNF1A expression. ...
Source: European Journal of Medical Genetics - April 20, 2020 Category: Genetics & Stem Cells Authors: Yau D, Colclough K, Natarajan A, Parikh R, Canham N, Didi M, Senniappan S, Banerjee I Tags: Eur J Med Genet Source Type: research

Novel EDAR mutation in tooth agenesis and variable associated features.
We report on 10 members of a Pakistani family afflicted with TA with variable associated features inherited in autosomal dominant fashion with full penetrance. The malformation is bilateral in the majority of cases, and hallmark feature is the absence of lateral and central incisors and canines whereas first and second premolars are involved less often. Affected individuals also have pronounced variable features associated with TA such as diastema between central incisors, overgrown labial frenum, peg-shaped lower incisors, delayed exfoliation, over-erupted upper incisors and malocclusion but have no other signs of ectoder...
Source: European Journal of Medical Genetics - April 20, 2020 Category: Genetics & Stem Cells Authors: Mumtaz S, Nalbant G, Bölükbaşı EY, Huma Z, Ahmad N, Tolun A, Malik S Tags: Eur J Med Genet Source Type: research

Shared facial phenotype of patients with mucolipidosis type IV: A clinical observation reaffirmed by next generation phenotyping.
CONCLUSIONS: We describe recognizable facial features typical in patients with ML-IV. Reaffirmed by the DeepGestalt technology, the described common facial phenotype adds to the tools currently available for clinicians and may thus assist in reaching an earlier diagnosis of this rare and underdiagnosed disorder. PMID: 32298796 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - April 13, 2020 Category: Genetics & Stem Cells Authors: Pode-Shakked B, Finezilber Y, Levi Y, Putter S, Fleischer N, Greenbaum L, Raas-Rothschild A Tags: Eur J Med Genet Source Type: research

Identification of a novel mutation in the MAFB gene in a pediatric patient with multicentric carpotarsal osteolysis syndrome using next-generation sequencing.
Abstract Multicentric carpotarsal osteolysis syndrome (MCTO) is a rare form of skeletal dysplasia characterized by progressive bone resorption, in the carpal and tarsal bones. Patients may develop chronic kidney disease, which eventually advances to end-stage renal disease (ESRD). Both sporadic and familial cases of autosomal-dominant inheritance are reported in literature. Here, we report a case of a 10.5-year-old boy who presented with CKD stage V, and who suffered from bone deformities and difficulty in walking at a younger age. He was diagnosed with MCTO and subjected to genetic analysis. We identified a novel...
Source: European Journal of Medical Genetics - April 9, 2020 Category: Genetics & Stem Cells Authors: Li J, Shi L, Lau K, Ma Y, Jia S, Gao X Tags: Eur J Med Genet Source Type: research

Molecular diagnosis of glycogen storage disease type IX using a glycogen storage disease gene panel.
Abstract Glycogen storage disease type IX (GSD IX) is caused by a deficiency of hepatic phosphorylase kinase. The aim of this study was to clarify the clinical features, long term outcomes, and genetic analysis of GSD IX in Korea. A GSD gene panel was created and hybridization capture-based next-generation sequencing was performed. We investigated clinical laboratory data, results of molecular genetic analysis, liver biopsy findings, and long-term outcomes. Ten children were diagnosed with GSD IX at Seoul National University Children's Hospital. Hypoglycemia, hyperlactacidemia, hypertriglyceridemia, hyperuricemia,...
Source: European Journal of Medical Genetics - March 31, 2020 Category: Genetics & Stem Cells Authors: Kim TH, Kim KY, Kim MJ, Seong MW, Park SS, Moon JS, Ko JS Tags: Eur J Med Genet Source Type: research

Severe craniofrontonasal syndrome in a male patient mosaic for a novel nonsense mutation in EFNB1.
Abstract Craniofrontonasal syndrome (CFNS) is an X-linked disorder caused by mutations in EFNB1. Uncommonly and paradoxically, female patients with CFNS exhibit significantly more severe symptoms than male patients. This is explained by "cellular interference". Nevertheless, there have been a few reports of male patients severely affected with CFNS due to postzygotic mosaicism. Here, we demonstrated a male patient with severe CFNS. Whole exome sequencing showed that he harbored both wild type and nonsense mutation, c.253C  >  T (p.Gln85Ter), in the EFNB1 gene. Sanger sequencing of his leukocyt...
Source: European Journal of Medical Genetics - March 30, 2020 Category: Genetics & Stem Cells Authors: Shotelersuk V, Kamolvisit W, Rojvachiranonda N, Suphapeetiporn K, Porntaveetus T, Shotelersuk V Tags: Eur J Med Genet Source Type: research

Mosaicism in ASXL3-related syndrome: Description of five patients from three families.
In this report, we present five patients with ASXL3-related syndrome, describing two families comprising two non-twin siblings harbouring apparent de novo pathogenic variants in ASXL3. Parents were clinically unaffected and there was no evidence of mosaicism from genomic DNA on exome-trio data, suggesting germline mosaicism in one of the parents. We also describe clinical details of a patient with typical features of ASXL3-related syndrome and mosaic de novo pathogenic variant in ASXL3 in 30-35% of both blood and saliva sample on trio-exome sequencing. We expand the known genetic basis of ASXL3-related syndromes and discus...
Source: European Journal of Medical Genetics - March 30, 2020 Category: Genetics & Stem Cells Authors: Schirwani S, Hauser N, Platt A, Punj S, Prescott K, Canham N, Study DDD, Mansour S, Balasubramanian M Tags: Eur J Med Genet Source Type: research

A child with complementary mosaic trisomy 8 and mosaic trisomy 21; clinical description of warkany-down syndrome and mechanism of origin.
Abstract Aneuploidy mosaicism involving two complementary different autosomal trisomy cell lines is extremely rare. Although a mosaic double trisomy 8/trisomy 21 has been described in literature, this is the first report of Warkany (+8)-Down (+21) syndrome due to two complementary mosaic trisomy cell lines. The phenotype of the male patient with Warkany-Down syndrome includes upslanting palpebral fissures, hypertelorism, small low-set ears with unilateral aural stenosis, large and broad hands and feet with deep palmar and plantar creases, bilateral cryptorchidism, generalized mild hypotonia and transient neonatal ...
Source: European Journal of Medical Genetics - March 30, 2020 Category: Genetics & Stem Cells Authors: McGregor-Schuerman M, Sang ALF, Bihari S, Ramdajal N, Suijkerbuijk RF, van Ravenswaaij-Arts CM Tags: Eur J Med Genet Source Type: research

A homozygote frameshift mutation in OCLN gene result in Pseudo-TORCH syndrome type I: A case report extending the phenotype with central diabetes insipidus and renal dysfunction.
Abstract Intrauterine infections with the pathogens, including toxoplasmosis, other (syphilis, varicella, mumps, parvovirus, and HIV), rubella, cytomegalovirus, and herpes simplex (TORCH) in susceptible individuals during pregnancy, result in microcephaly, white matter disease, cerebral atrophy, and calcifications in the fetus. Pseudo-TORCH syndrome is an umbrella term, consisting of several syndromes, resultant from different genetic alterations and pathogenetic mechanisms. Band-like calcification with simplified gyration and polymicrogyria (BLC-PMG) is one of these conditions, resultant from biallelic mutations ...
Source: European Journal of Medical Genetics - March 30, 2020 Category: Genetics & Stem Cells Authors: Ekinci F, Yildizdas RD, Horoz OO, Herguner O, Bisgin A Tags: Eur J Med Genet Source Type: research

Genetic diagnosis of autoinflammatory disease patients using clinical exome sequencing.
Arostegui JI, Casals F Abstract Autoinflammatory diseases comprise a wide range of syndromes caused by dysregulation of the innate immune response. They are difficult to diagnose due to their phenotypic heterogeneity and variable expressivity. Thus, the genetic origin of the disease remains undetermined for an important proportion of patients. We aim to identify causal genetic variants in patients with suspected autoinflammatory disease and to test the advantages and limitations of the clinical exome gene panels for molecular diagnosis. Twenty-two unrelated patients with clinical features of autoinflammatory dise...
Source: European Journal of Medical Genetics - March 25, 2020 Category: Genetics & Stem Cells Authors: Batlle-Masó L, Mensa-Vilaró A, Solís-Moruno M, Marquès-Bonet T, Arostegui JI, Casals F Tags: Eur J Med Genet Source Type: research

1p31.1 microdeletion including only NEGR1 gene in two patients.
Abstract Neuronal growth regulator 1 (NEGR1), a member of the immunoglobulin superfamily cell adhesion molecule subgroup IgLON, has been involved in neuronal growth and connectivity. Genetic variants, in or near the NEGR1 locus, have been associated with obesity and, more recently, with learning difficulties, intellectual disability, and psychiatric disorders. Here, we described the only second report of NEGR1 gene disruption in 1p31.1 microdeletion in two patients. Patient 1 is a 14-year-old female with neurological and psychiatric features present also in her family. Patient 2 is a 5-month-old infant showing glo...
Source: European Journal of Medical Genetics - March 21, 2020 Category: Genetics & Stem Cells Authors: Tassano E, Uccella S, Giacomini T, Fiorio P, Tavella E, Malacarne M, Gimelli G, Coviello D, Ronchetto P Tags: Eur J Med Genet Source Type: research

A familial PLCB4 mutation causing auriculocondylar syndrome 2 with variable severity.
This report increases the number of molecularly characterized ARCND patients to 29 and emphasizes the highly variable clinical presentation within families. PMID: 32201334 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - March 19, 2020 Category: Genetics & Stem Cells Authors: Nabil A, El Shafei S, El Shakankiri NM, Habib A, Morsy H, Maddirevula S, Alkuraya FS Tags: Eur J Med Genet Source Type: research

Microcoria due to first duplication of 13q32.1 including the GPR180 gene and maternal mosaicism.
We present a detailed clinical examination and follow up. DNA from the index patient was analyzed for the presence of chromosomal imbalances using molecular karyotyping. The genetic test revealed a small duplication of chromosome band 13q32.1. The duplication affected a 289 kb region, encompassing 11 genes including GPR180. Interestingly, the patient displays only MCOR in contrast to patients with the reciprocal deletion who present with MCOR and iridocorneal angle dysgenesis. This genetic anomaly was inherited from the mother who carries the duplication in mosaic form, which should be considered when offering genetic co...
Source: European Journal of Medical Genetics - March 18, 2020 Category: Genetics & Stem Cells Authors: Pozza E, Verdin H, Deconinck H, Dheedene A, Menten B, De Baere E, Balikova I Tags: Eur J Med Genet Source Type: research

Imprinted genes in clinical exome sequencing: Review of 538 cases and exploration of mouse-human conservation in the identification of novel human disease loci.
Abstract Human imprinting disorders cause a range of dysmorphic and neurocognitive phenotypes, and they may elude traditional molecular diagnosis such exome sequencing. The discovery of novel disorders related to imprinted genes has lagged behind traditional Mendelian disorders because current diagnostic technology, especially unbiased testing, has limited utility in their discovery. To identify novel imprinting disorders, we reviewed data for every human gene hypothesized to be imprinted, identified each mouse ortholog, determined its imprinting status in the mouse, and analyzed its function in humans and mice. W...
Source: European Journal of Medical Genetics - March 10, 2020 Category: Genetics & Stem Cells Authors: Bhoj EJ, Rajabi F, Baker SW, Santani A, Tan WH Tags: Eur J Med Genet Source Type: research

Answer to Finsterer about "Multisystem presentation of a homozygous POLG2 variant".
Answer to Finsterer about "Multisystem presentation of a homozygous POLG2 variant". Eur J Med Genet. 2020 Mar 09;:103900 Authors: Dosekova P, Dubiel A, Karlowicz A, Zietkiewicz S, Rydzanicz M, Habalova V, Pienkowski VM, Skirkova M, Han V, Mosejova A, Gdovinova Z, Kaliszewska M, Tońska K, Szymanski MR, Skorvanek M, Ploski R PMID: 32165262 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - March 9, 2020 Category: Genetics & Stem Cells Authors: Dosekova P, Dubiel A, Karlowicz A, Zietkiewicz S, Rydzanicz M, Habalova V, Pienkowski VM, Skirkova M, Han V, Mosejova A, Gdovinova Z, Kaliszewska M, Tońska K, Szymanski MR, Skorvanek M, Ploski R Tags: Eur J Med Genet Source Type: research

Multisystem presentation of a homozygous POLG2 variant.
PMID: 32156559 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - March 7, 2020 Category: Genetics & Stem Cells Authors: Finsterer J Tags: Eur J Med Genet Source Type: research

Clues and challenges in the diagnosis of intermittent maple syrup urine disease.
CONCLUSIONS: While newborn screening programs allow for early detection of classic MSUD, cases of the intermittent form might go undetected, and present later in childhood following metabolic derailment, with an array of non-specific symptoms. Our experience with the families reported herein adds to the current knowledge regarding the phenotype and mutational spectrum of this unique inborn error of branched-chain amino acid metabolism, and underscore the high index of suspicion required for its diagnosis. PMID: 32151765 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - March 6, 2020 Category: Genetics & Stem Cells Authors: Pode-Shakked N, Korman SH, Pode-Shakked B, Landau Y, Kneller K, Abraham S, Shaag A, Ulanovsky I, Daas S, Saraf-Levy T, Reznik-Wolf H, Vivante A, Pras E, Almashanu S, Anikster Y Tags: Eur J Med Genet Source Type: research

Novel truncating and missense variants extending the spectrum of EMC1-related phenotypes, causing autism spectrum disorder, severe global development delay and visual impairment.
We report a ten-year-old boy, born to unrelated parents, with early-onset severe global development delay due to novel EMC1 biallelic pathogenic variants. A truncating variant, p.(Tyr378*) and a missense variant, p.(Phe953Ser), located in exon 11 and 23 of EMC1 gene respectively, have been found by reanalysis of exome sequencing data. The proband's phenotype included several signs that overlap with the phenotype of previously reported patients, associating severe global developmental delay, abnormal ophthalmological examination, and postnatal slow-down of the head circumference growth. Some distinguishing clinical signs we...
Source: European Journal of Medical Genetics - February 21, 2020 Category: Genetics & Stem Cells Authors: Cabet S, Lesca G, Labalme A, Portes VD, Guibaud L, Sanlaville D, Pons L Tags: Eur J Med Genet Source Type: research

Expansion of the phenotype of biallelic variants in TRIT1.
PMID: 32088416 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - February 20, 2020 Category: Genetics & Stem Cells Authors: Forde KM, Buckley PG, Conroy J, Green AJ, King MD, Molloy B, Ryan S, Gorman KM Tags: Eur J Med Genet Source Type: research