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European Journal of Medical Genetics

Evgeny Suspitsin, Anna Sokolenko, Ilya Bizin, Anastasia Tumakova, Marina Guseva, Natalia Sokolova, Svetlana Vakhlyarskaya, Irina Kondratenko, Evgeny Imyanitov
Ataxia-telangiectasia (AT) is a severe autosomal recessive orphan disease characterized by a number of peculiar clinical manifestations. Genetic diagnosis of AT is complicated due to a large size of the causative gene, ATM. We used next-generation sequencing (NGS) technology for the ATM analysis in 17 children with the clinical diagnosis of AT. Biallelic mutations in the ATM gene were identified in all studied subjects; these lesions included one large gene rearrangement, which was reliably detected by NGS and validated by multiplex ligation-dependent probe amplification (MLPA)...
February 14, 2019: European Journal of Medical Genetics
M Kuersten, M Tacke, L Gerstl, H Hoelz, C V Stülpnagel, I Borggraefe
BACKGROUND: KCNQ2 related disorders comprise both benign seizure disorders and early onset epileptic encephalopathies. Especially within the latter group, patients suffer from refractory seizures to standard antiepileptic drugs and developmental delay. Besides the hope of personalized medical approaches to treat the recently unraveled large amount of genetic channelopathies, there are sparse systematic data on treatment responses in KCNQ2 related epilepsy in larger cohorts. METHODS: We searched PubMed using the free text term search 'KCNQ2 AND Epilepsy' and identified additional records using PubMed Medical Subject Headings (MeSH)...
February 13, 2019: European Journal of Medical Genetics
Reyhaneh Kameli, Mahmoud Reza Ashrafi, Farveh Ehya, Houman Alizadeh, Sareh Hosseinpour, Masoud Garshasbi, Ali Reza Tavasoli
RIN2 syndrome also known as MACS syndrome is a rare autosomal recessive connective tissue disorder caused by RIN2 mutations and is accompanied by following clinical features: macrocephaly, coarsening of facial features, downward slanting palpebral fissures, Puffy droopy eyelids, full everted lips, soft redundant skin especially in face, gum hypertrophy, irregular dentition, sparse scalp hair, skeletal problems, joint hypermobility and scoliosis. RIN2 gene encodes the RAS and RAB interactor 2 and biallelic mutations in this gene cause cell trafficking dysfunction...
February 12, 2019: European Journal of Medical Genetics
Annarita Giliberti, Aurora Currò, Filomena Tiziana Papa, Elisa Frullanti, Francesca Ariani, Coriolani Gianni, Salvatore Grosso, Alessandra Renieri, Francesca Mari
Myeloid ecotropic insertion site 2 (MEIS2) gene, encoding a homeodomain-containing transcription factor, has been recently related to syndromic intellectual disability with cleft palate and cardiac defects. Here, we present a male patient, aged 10, with cardiac defects, intellectual disability, facial dysmorphisms and gastroesophageal reflux. Whole exome sequencing revealed a novel de novo nonsense mutation in the MEIS2 gene. This patient represents another reported case with a de novo MEIS2 point mutation and helps to characterize a distinct facial phenotype consisting in low anterior hairline, thin eyebrows, anteverted nares, hypoplastic alae nasi, and M-shape upper lip...
February 5, 2019: European Journal of Medical Genetics
Sarah Dorval, Maura Masciadri, Mikaël Mathot, Silvia Russo, Nicole Revencu, Lidia Larizza
Cornelia de Lange syndrome is a rare autosomal dominant or X-linked developmental disorder characterized by characteristic facial dysmorphism, intellectual disability, growth retardation, upper limb and multiorgan anomalies. Causative mutations have been identified in five genes coding for the cohesion complex structure components or regulatory elements. Among them, RAD21 is associated with a milder phenotype. Very few RAD21 intragenic mutations have been identified so far. Thus, any new patient is a valuable tool to delineate the associated phenotype...
February 1, 2019: European Journal of Medical Genetics
Akito Sutani, Hirohito Shima, Atsushi Hijikata, Susumu Hosokawa, Yuko Fukui, Kei Takasawa, Erina Suzuki, Shozaburou Doi, Tsuyoshi Shirai, Tomohiro Morio, Maki Fukami, Kenichi Kashimada
10q26 deletion syndrome is caused by a rare chromosomal abnormality, and patients with this syndrome present with an extensive and heterogeneous phenotypic spectrum. Several genes, such as EMX2 and FGFR2, were identified to cause genital anomalies and facial dysmorphism of 10q26 deletion syndrome. However, the critical region for 10q26 deletion syndrome is not determined and the precise relationships between the causative genes and the phenotypes are still controversial. WD repeat domain 11 (WDR11), located at 10q25-26, was recently identified as a causative gene in hypogonadotropic hypogonadism, but other clinical phenotypes caused by WDR11 variants have not been identified...
January 31, 2019: European Journal of Medical Genetics
Mark McCormack, Ronan McGinty, Xiaolin Zhu, Lisa Slattery, Erin L Heinzen, Daniel J Costello, Norman Delanty, Gianpiero L Cavalleri
We set out to investigate whether a de-novo paradigm could explain genetic causes of chronic ultra-refractory epilepsy, with onset later than the typical age for the epileptic encephalopathies. We performed exome sequencing on nine adult patients with MRI-negative epilepsy and no preceding intellectual disability. All had an onset of seizures after five years old and had chronic ultra-refractory epilepsy defined here as having failed more than six anti-epileptic drugs and currently experiencing ≥4 disabling seizures per month...
January 31, 2019: European Journal of Medical Genetics
Marie Šedivá, Petra Laššuthová, Josef Zámečník, Lucie Sedláčková, Pavel Seeman, Jana Haberlová
Birk Barel syndrome also known as KCNK9 imprinting syndrome is a rare developmental disorder associated with a loss-of-function variant in KCNK9, an imprinted gene with maternal expression on the 8th chromosome encoding the TASK3 (TWIK-related acidity inhibited K + -channel 3). Only two variants of KCNK9 have been associated with this condition before, both of them leading to the same amino-acid exchange p.Gly236Arg (Barel ´ 2008, Graham ´ 2016). We describe a case of a 17-year-old girl presenting with very similar phenotype and pure motor neuropathy with a novel variant c...
January 25, 2019: European Journal of Medical Genetics
Fabiola P Monteiro, Cynthia J Curry, Robert Hevner, Stephen Elliott, Jamie H Fisher, John Turocy, William B Dobyns, Larissa A Costa, Erika Freitas, João Paulo Kitajima, Fernando Kok
The Na+ /K+ - ATPase acts as an ion pump maintaining the essential plasma membrane potential in all mammalian cell types, and is essential for many cellular functions. There are four α isoforms (α1, α2, α3 and α4) with distinct expression patterns, kinetic properties and substrate affinity. The α2-isoform is encoded by ATP1A2 and evidence supports its utmost importance in Cl- homeostasis in neurons, and in the function of respiratory neurons at birth. Monallelic pathogenic variants in ATP1A2 are associated with familial hemiplegic migraine type 2 (FHM2) and on rare occasions with alternating hemiplegia of childhood 1 (AHC1)...
January 25, 2019: European Journal of Medical Genetics
Sami Bizzari, Abdul Rezzak Hamzeh, Madiha Mohamed, Mahmoud Taleb Al-Ali, Fatma Bastaki
Pontocerebellar Hypoplasia type 1 is a rare heterogeneous neurodegenerative disorder with multiple subtypes linked to dysfunction of the exosome complex. Patients with mutations in exosome subunits exhibit a generally lethal phenotype characterized by cerebellar and pontine hypoplasia in association with spinal motor neuropathy and multiple systemic and neurologic features. Recently, two variants in the novel PCH1 associated protein EXOSC9 p.(Leu14Pro) and p.(Arg161*) have been identified in 4 unrelated patients exhibiting a severe phenotype involving cerebellar hypoplasia, axonal motor neuropathy, hypotonia, feeding difficulties, and respiratory insufficiency (PCH1D)...
January 25, 2019: European Journal of Medical Genetics
Mathew J Wallis, Amber Boys, Elisa Tassano, Martin B Delatycki
A small heterozygous deletion involving KANK1 was originally reported in 2005 to cause cerebral palsy in one large Israeli family of Jewish Moroccan origin. There were nine affected children over two generations to five unaffected fathers. All of these children had congenital hypotonia that evolved into spastic quadriplegia over the first year of life, along with intellectual impairment and brain atrophy. The subsequent clinical depictions of other individuals with neurological disease harbouring a comparable KANK1 deletion have been extremely variable and most often quite dissimilar to the original family...
January 23, 2019: European Journal of Medical Genetics
Kun Li, Runming Jin, Xiaoyan Wu
Human MSTO1 is involved in the regulation of mitochondrial distribution and morphology and its unregulated expression leads to mitochondrial disorder. Despite its significance for mitochondrial functions, human MSTO1 gene is rarely studied before 2017. As of late, MSTO1 mutations have been reported to cause clinical manifestations such as myopathy, cerebellar atrophy and ataxia, motor developmental delay, and pigmentary retinopathy. Here we have performed a whole-exome sequencing in a family which includes two brothers showing cerebellar atrophy and ataxia, intellectual disability, and myopathy...
January 23, 2019: European Journal of Medical Genetics
Zeynep Yuruk Yildirim, Guven Toksoy, Oya Uyguner, Ahmet Nayir, Sevgi Yavuz, Umut Altunoglu, Ozde Nisa Turkkan, Burcu Sevinc, Gulden Gokcay, Dilek Kurkcu Gunes, Aysel Kiyak, Alev Yilmaz
Primary coenzyme Q10 deficiency-6 (COQ10D6) is a rare autosomal recessive disorder caused by COQ6 mutations. The main clinical manifestations are infantile progressive nephrotic syndrome (NS) leading to end-stage renal disease and sensorineural deafness. A 7-year-old girl was diagnosed with steroid-resistant NS (SRNS) and an audiological work-up revealed bilateral sensorineural deafness. A renal biopsy demonstrated focal segmental glomerulosclerosis. Despite immunosuppressive therapy, her serum levels of creatinine increased and haemodialysis was indicated within 1 year after the diagnosis...
January 22, 2019: European Journal of Medical Genetics
Zoran Gucev, Velibor Tasic, Ivona Bogevska, Nevenka Laban, Alek Saveski, Momir Polenakovic, Dijana Plasevska-Karanfilska, Katalin Komlosi, Jennifer Winter, Susann Schweiger, Gen Nishimura, Jürgen Spranger, Oliver Bartsch
Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV (HSAN-IV), is a rare and severe autosomal recessive disorder. We report on an adult female patient whose clinical findings during childhood were not recognized as CIPA. There was neither complete anhidrosis nor a recognizable sensitivity to heat. Tumorlike swellings of many joints and skeletal signs of Charcot neuropathy developed in adolescence which, together with a history of self-mutilation, led to a clinical suspicion of CIPA confirmed by identification of a novel homozygous variant c...
January 21, 2019: European Journal of Medical Genetics
Adeline Jacquinet, Adeline Bonnard, Yline Capri, Didier Martin, Bernard Sadzot, Elettra Bianchi, Laurent Servais, Jean-Paul Sacré, Hélène Cavé, Alain Verloes
Mutations in LZTR1, already known to be causal in familial schwannomatosis type 2, have been recently involved in a small proportion of patients with autosomal dominant and autosomal recessive Noonan syndrome. LZTR1 is also a driver gene in non syndromal glioblastoma. We report a 26-year-old patient with typical Noonan syndrome, and the dominantly transmitted c.850C > T (p.(Arg284Cys)) variant in LZTR1. An oligoastrocytoma was diagnosed in the patient at the age of 22 years; recurrence of the tumor occurred at age 26, as a ganglioblastoma...
January 18, 2019: European Journal of Medical Genetics
Alexandra Benachi, Jessica Caffrey, Pavel Calda, Elena Carreras, Jacques Jani, Mark Kilby, Hanns-Georg Klein, Giuseppe Rizzo, Yuval Yaron
Cell-free DNA-based noninvasive prenatal testing (cfDNA) is a relatively new screening tool that analyzes cfDNA circulating in maternal plasma to screen for aneuploidies. Since its introduction, cfDNA has been rapidly adopted by health care providers (HCPs). This rapid adoption, as well as progressive developments in the technology, requires professional societies to continuously update their guidelines to indicate the broadening scope both in terms of test indications and patient populations for whom it has become the appropriate primary test...
January 14, 2019: European Journal of Medical Genetics
Gianluca Tornese, Maria Chiara Pellegrin, Egidio Barbi, Alessandro Ventura
In everyday practice, a pediatric endocrinologist will face a variety of different endocrine issues (such as short or tall stature, dysthyroidism, abnormal pubertal timing or impaired glucose metabolism), which relevantly contribute to the global care of a number of syndromic conditions. On the other hand, the presence of endocrine features may assist in the diagnostic process, leading to final diagnosis of a syndromic disorder. The intention of this review is to provide a referenced overview of different genetic syndromes characterized by endocrine features, and to present a possible classification, based on whether the endocrinopathy or the syndrome is typically recognized first...
January 14, 2019: European Journal of Medical Genetics
Mohammad M Al-Qattan, Sateesh Maddirevula, Fowzan S Alkuraya
Ulnar-mammary syndrome (UMS) is a rare syndromic limb malformation caused by heterozygous mutations in TBX3. The name highlights the two commonly involved body parts i.e. mammary gland and ulnar ray of the upper limbs, although a more extensive systemic involvement is also known to occur. Here, we report the surprising finding of a patient with a de novo mutation in TBX3 whose clinical presentation is limited to dorsalization of both little fingers and slightly deep 4th web spaces. We review the literature to confirm that this should be considered as a forme fruste phenotype of UMS...
January 14, 2019: European Journal of Medical Genetics
Amélie Stern-Delfils, Marie-Aude Spitz, Myriam Durand, Cathy Obringer, Nadège Calmels, Jérôme Olagne, Komala Pillay, Karen Fieggen, Vincent Laugel, Ariane Zaloszyc
BACKGROUND: Cockayne Syndrome (CS) is a rare autosomal recessive multi-systemic disorder, characterized; by developmental delay, microcephaly, severe growth failure and sensorial impairment. Renal complications have been reported but remain underinvestigated. The objective of this study was to perform a review of renal disease in a cohort of CS patients. METHODS: We retrospectively collected relevant clinical, biochemical and genetic data from a cohort of 136 genetically confirmed CS patients...
January 7, 2019: European Journal of Medical Genetics
Qingming Wang, Xiaoling Huang, Yanhui Liu, Qian Peng, Yuqiong Zhang, Jianxin Liu, Haiming Yuan
Xia-Gibbs syndrome is a rare genetic condition characterized by intellectual disability, growth retardation, delayed psychomotor development with absent or poor expressive language, distinctive facial features, hypotonia, laryngomalacia and obstructive sleep apnea. At present, Xia-Gibbs syndrome has been reported to be mainly caused by truncating mutations in AHDC1 gene located on chromosome 1p36.11. However, the evidence supporting AHDC1 deletion as a cause of this syndrome is still limited. Here we report an 8-year-old boy carrying a de novo 575 Kb microdeletion at 1p36...
January 4, 2019: European Journal of Medical Genetics
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