Alkaptonuria in Russia: mutational spectrum and novel variants
Eur J Med Genet. 2021 Feb 20:104165. doi: 10.1016/j.ejmg.2021.104165. Online ahead of print.ABSTRACTAlkaptonuria is a rare genetic disease caused by mutations in HGD gene. Here we report the results of genetic and biochemical analysis of 49 Russian patients with alkaptonuria. One of the common variants c.481G>A; p.(Gly161Arg) comprising 72.4% of identified alleles was found in 45 of 49 patients in our cohort, which is probably the highest frequency of this variant worldwide. 9 novel variants were found: 8 missense, 2 splicing and 1 loss of start-codon. For missense variants we performed bioinformatic analysis, protein 3...
Source: European Journal of Medical Genetics - February 23, 2021 Category: Genetics & Stem Cells Authors: Igor Bychkov Elena Kamenets Marina Kurkina Georgiy Rychkov Alexandra Ilyushkina Aleksandra Filatova Darya Guseva Galina Baydakova Andrey Nekrasov Aleksandr Cheblokov Mikhail Skoblov Ekaterina Zakharova Source Type: research

Alkaptonuria in Russia: mutational spectrum and novel variants
Eur J Med Genet. 2021 Feb 20:104165. doi: 10.1016/j.ejmg.2021.104165. Online ahead of print.ABSTRACTAlkaptonuria is a rare genetic disease caused by mutations in HGD gene. Here we report the results of genetic and biochemical analysis of 49 Russian patients with alkaptonuria. One of the common variants c.481G>A; p.(Gly161Arg) comprising 72.4% of identified alleles was found in 45 of 49 patients in our cohort, which is probably the highest frequency of this variant worldwide. 9 novel variants were found: 8 missense, 2 splicing and 1 loss of start-codon. For missense variants we performed bioinformatic analysis, protein 3...
Source: European Journal of Medical Genetics - February 23, 2021 Category: Genetics & Stem Cells Authors: Igor Bychkov Elena Kamenets Marina Kurkina Georgiy Rychkov Alexandra Ilyushkina Aleksandra Filatova Darya Guseva Galina Baydakova Andrey Nekrasov Aleksandr Cheblokov Mikhail Skoblov Ekaterina Zakharova Source Type: research

Symptomatic heterozygous X-Linked Myotubular Myopathy female patient with a large deletion at Xq28 and decrease expression of normal allele
Eur J Med Genet. 2021 Feb 19:104170. doi: 10.1016/j.ejmg.2021.104170. Online ahead of print.ABSTRACTX-linked myotubular myopathy (XLMTM; OMIM 310400) is a centronuclear congenital muscular disorder of X-linked recessive inheritance. Although female carriers are typically asymptomatic, affected heterozygous females have been described. Here, we describe the case of a sporadic female patient with suspicion of centronuclear myopathy and a heterozygous large deletion at Xq28 encompassing the MAMLD1, MTM1, MTMR1, CD99L2, and HMGB3 genes. The deletion was first detected using a custom next generation sequencing (NGS)-based multi...
Source: European Journal of Medical Genetics - February 22, 2021 Category: Genetics & Stem Cells Authors: Clara G ómez-González Roc ío Rosas Carlos Rodr íguez-Antolín Alvaro Garc ía-Guede Inmaculada Ib áñez de Caceres Javier Sanguino Samuel I Pascual Isabel Esteban Angela Del Pozo Mar ía Ángeles Mori Rosa J Torres Carmen Prior Source Type: research

The contribution of Xp22.31 gene dosage to Turner and Klinefelter syndromes and sex-biased phenotypes
Eur J Med Genet. 2021 Feb 18:104169. doi: 10.1016/j.ejmg.2021.104169. Online ahead of print.ABSTRACTTurner syndrome (TS) is a rare developmental condition in females caused by complete, or partial, loss of the second sex chromosome; it is associated with a number of phenotypes including short stature, ovarian failure and infertility, as well as neurobehavioural and cognitive manifestations. In contrast, Klinefelter syndrome (KS) arises from an excess of X chromosome material in males (typical karyotype is 47,XXY); like TS, KS is associated with infertility and hormonal imbalance, and behavioural/neurocognitive differences ...
Source: European Journal of Medical Genetics - February 21, 2021 Category: Genetics & Stem Cells Authors: William Davies Source Type: research

Clinical practice of a genetics referral selection tool in pediatric cancer patients
In this study, we used a previously proposed patient selection tool by Jongmans and discussed the findings in regard to pediatric cancer patients we treated. Pediatric solid tumor patients who were treated in Kocaeli University Department of Pediatric Oncology were evaluated with the five main questions in Jongmans' referral tool. All of the patients and records of diagnostic imaging were examined and analyzed. One-hundred-twenty-three patients participated in the study. The most common indication for genetic counseling was 'consanguinity of the parents' with '≥2 malignancies at childhood age' following it. Fifty-two (4...
Source: European Journal of Medical Genetics - February 15, 2021 Category: Genetics & Stem Cells Authors: Ugur Demirsoy Funda Corapcioglu Source Type: research

Clinical practice of a genetics referral selection tool in pediatric cancer patients.
In this study, we used a previously proposed patient selection tool by Jongmans and discussed the findings in regard to pediatric cancer patients we treated. Pediatric solid tumor patients who were treated in Kocaeli University Department of Pediatric Oncology were evaluated with the five main questions in Jongmans' referral tool. All of the patients and records of diagnostic imaging were examined and analyzed. One-hundred-twenty-three patients participated in the study. The most common indication for genetic counseling was 'consanguinity of the parents' with '≥2 malignancies at childhood age' following it. Fifty-two (4...
Source: European Journal of Medical Genetics - February 12, 2021 Category: Genetics & Stem Cells Authors: Demirsoy U, Corapcioglu F Tags: Eur J Med Genet Source Type: research

Severe congenital contractural arachnodactyly caused by biallelic pathogenic variants in FBN2.
AE Abstract Fibrillin-2, encoded by FBN2, plays an important role in the early process of elastic fiber assembly. To date, heterozygous pathogenic variants in FBN2 have been shown to cause congenital contractural arachnodactyly (CCA; Beals-Hecht syndrome). Classical CCA is characterized by long and slender fingers and toes, ear deformities, joint contractures at birth, clubfeet, muscular hypoplasia and often tall stature. In individuals with a severe CCA form, different cardiovascular or gastrointestinal anomalies have been described. Here, we report on a 15-year-old girl with a severe form of CCA and novel biall...
Source: European Journal of Medical Genetics - February 8, 2021 Category: Genetics & Stem Cells Authors: Kloth K, Neu A, Rau I, Hülsemann W, Kutsche K, Volk AE Tags: Eur J Med Genet Source Type: research

'More than a Box of Puzzles': Understanding the Parental Experience of Having a Child with a Rare Genetic Condition".
CONCLUSION: This study highlights the importance of considering the parental perspective in the context of genetic testing in clinical practice. PMID: 33571692 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - February 8, 2021 Category: Genetics & Stem Cells Authors: Fitzgerald J, Wilson C, Kelly C, Gallagher L Tags: Eur J Med Genet Source Type: research

Abnormal auditory event-related potentials in Williams syndrome.
Abstract Individuals with Williams Syndrome (WS) have specific auditory characteristics, including hypoacusis and hyperacusis, and music appreciation skills. Little is known about the functionality of the central auditory nervous system (CANS) for sound processing in WS. Thus, the objective of the present study was to evaluate the functionality of the CANS in individuals with WS, based on auditory event-related potentials, as far as cognitive and behavioral aspects are concerned. The study was carried out with 17 individuals, seven females and ten males, between seven and 17 years old, with WS, and 17 individuals ...
Source: European Journal of Medical Genetics - February 8, 2021 Category: Genetics & Stem Cells Authors: Fagundes Silva LA, Honjo Kawahira RS, Kim CA, Matas CG Tags: Eur J Med Genet Source Type: research

Hypersociability associated with developmental delay, macrocephaly and facial dysmorphism points to CHD3 mutations.
We report the clinical description of a 21-year-old patient harboring a pathogenic de novo variant in CHD3. We reviewed the clinical features of the 35 previously reported patients. Main features were severe intellectual disability, dysmorphic facies, macrocephaly, cryptorchidism, pectus carinatum, severe ophthalmologic abnormalities and behavioral disorders including ASD, and a frank happy demeanor. Hypersociability, which was a noticeable clinical feature in our case, despite ASD, is an uncommon behavioral feature in syndromic intellectual disabilities. Our report supports hypersociability as a suggestive feature of CHD3...
Source: European Journal of Medical Genetics - February 8, 2021 Category: Genetics & Stem Cells Authors: Coursimault J, Lecoquierre F, Saugier-Veber P, Drouin-Garraud V, Lechevallier J, Boland A, Deleuze JF, Frebourg T, Nicolas G, Brehin AC Tags: Eur J Med Genet Source Type: research

Early prenatal presentation of the cartilage-hair hypoplasia / anauxetic dysplasia spectrum of disorders mimicking recurrent thanatophoric dysplasia.
Abstract Three sibling fetuses identified with limb shortening and thoracic narrowing at twelve weeks' gestation on first trimester ultrasound examination are presented. The parents were non-consanguineous, Caucasian, healthy, of normal stature and had a healthy normal daughter. The radiographic abnormalities were highly suggestive of thanatophoric dysplasia, but molecular analysis failed to identify a pathogenic variant in FGFR3. The three fetuses were found to have identical compound heterozygous mutations in RMRP in trans, one inherited from the mother and one from the father. This represents the early prenatal...
Source: European Journal of Medical Genetics - February 7, 2021 Category: Genetics & Stem Cells Authors: Hall CM, Liu B, Haworth A, Reed L, Pryce J, Mansour S Tags: Eur J Med Genet Source Type: research

Polycystic liver disease genes: practical considerations for genetic testing.
Abstract The development of a polycystic liver is a characteristic of the monogenic disorders: autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), and autosomal dominant polycystic liver disease (ADPLD). Respectively two and one genes mainly cause ADPKD and ARPKD. In contrast, ADPLD is caused by at least six different genes which combined do not even explain the disease development in over half of the ADPLD population. Genetic testing is mainly performed to confirm the likelihood of developing PKD and if renal therapy is essential. However, pure ADPLD patien...
Source: European Journal of Medical Genetics - February 5, 2021 Category: Genetics & Stem Cells Authors: Boerrigter MM, Bongers EMHF, Lugtenberg D, Nevens F, Drenth JPH Tags: Eur J Med Genet Source Type: research

GREB1L as a Candidate Gene of Mayer-Rokitansky-K üster-Hauser Syndrome.
GREB1L as a Candidate Gene of Mayer-Rokitansky-Küster-Hauser Syndrome. Eur J Med Genet. 2021 Feb 03;:104158 Authors: Barffour IK, Baah Kwarkoh RK Abstract Mayer-Rokitansky-Küster-Hauser (MRKH) Syndrome is a sex development disorder that affects 1 in every 4,500 live 46, XX female births. At least a subset of MRKH syndrome is genetically related and many candidate genes have been identified. The growth regulation by estrogen in breast cancer 1-like gene (GREB1L) is an androgen-regulated gene reported as a co-activator of the retinoic acid receptor gene (RAR). Thus expression levels of GREB1L ...
Source: European Journal of Medical Genetics - February 3, 2021 Category: Genetics & Stem Cells Authors: Barffour IK, Baah Kwarkoh RK Tags: Eur J Med Genet Source Type: research

A 3'-truncating FTL mutation associated with hypoferritinemia without neuroferritinopathy.
We report on a FTL mutation in a three generation family with autosomal dominant hypoferritinemia without neurodegeneration. The 4 year old proband was identified with longstanding history of hypoferritinemia without evidence of anemia. Brain MRI did not show any evidence of iron deposition. It was found that the patient's 19 month old sister, 30 year old mother and 58 year old maternal grandmother also had hypoferritinemia and normal iron levels. Over the next six years, none of these persons had any evidence of neurological dysfunction, including movement disorders, gait disturbances, behavioral or psychiatric dysfunctio...
Source: European Journal of Medical Genetics - February 3, 2021 Category: Genetics & Stem Cells Authors: Turner S, Dress C, Misra VK Tags: Eur J Med Genet Source Type: research

Novel truncating mutations in ASXL1 identified in two Chinese boys with Bohring-Opitz syndrome.
Abstract Bohring-Opitz syndrome (BOS, or BOPS) is a rare congenital genetic disorder with multisystem abnormalities characterized by significant craniofacial dysmorphism, feeding difficulties, severe developmental delay, profound intellectual disability, flexion of elbows with ulnar deviation, and flexion of the wrists and metacarpophalangeal joints. Here, we report two Chinese BOS patients with distinctive phenotypes caused by novel truncating mutations. One was a boy aged 5 years 9 months who had a novel c.1049G>A/p.Trp350* mutation in ASXL1 and who displayed relatively mild BOS symptoms with autism features....
Source: European Journal of Medical Genetics - January 30, 2021 Category: Genetics & Stem Cells Authors: Zhao J, Hou Y, Fang F, Ding C, Yang X, Li J, Cui D, Cao Z, Zhang H Tags: Eur J Med Genet Source Type: research

Genetic counseling for women with 45,X/46,XX mosaicism: Towards more personalized management.
in AE Abstract Despite numerous clinical series, consistent karyotype-phenotype correlations for Turner syndrome have not been established, although a lower level of 45,X is generally thought to be associated with a milder phenotype. This limits personalized counseling for women with 45,X/46,XX mosaicism. To better understand the phenotypic spectrum associated with various levels of 45,X/46,XX mosaicism, we compared patients evaluated in the Massachusetts General Hospital Turner Syndrome Clinic to determine if cardiac, renal, and thyroid abnormalities correlated with the percentage of 45,X cells present in a perip...
Source: European Journal of Medical Genetics - January 29, 2021 Category: Genetics & Stem Cells Authors: Snyder EA, San Roman AK, Piña-Aguilar RE, Steeves MA, McNamara EA, Souter I, Hayes FJ, Levitsky LL, Lin AE Tags: Eur J Med Genet Source Type: research

Corrigendum to UFSP2-related spondyloepimetaphyseal dysplasia: A confirmatory report [European Journal of Medical Genetics, (2020) Nov; 63(11): 104021].
PMID: 33514497 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - January 27, 2021 Category: Genetics & Stem Cells Authors: Zhang G, Tang S, Wang H, Pan H, Zhang W, Huang Y, Kong J, Wang Y, Gu J, Wang Y Tags: Eur J Med Genet Source Type: research

NGLY1 deficiency: Novel variants and literature review.
We describe five patients from two families with NGLY1 deficiency due to homozygosity for two novel NGLY1 variants, and compare their findings to those of earlier reported patients. The typical features of the disorder are present in a limited way, and there is intra-familial variability. In addition in one of the families the muscle atrophy and posture abnormalities are marked. These can be explained either as variability of the phenotype or as sign of slowly progression of features as the present affected individuals are older than earlier reported patients. PMID: 33497766 [PubMed - as supplied by publisher] (Source...
Source: European Journal of Medical Genetics - January 23, 2021 Category: Genetics & Stem Cells Authors: Kariminejad A, Shakiba M, Shams M, Namiranian P, Eghbali M, Talebi S, Makvand M, Jaeken J, Najmabadi H, Hennekam RC Tags: Eur J Med Genet Source Type: research

Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency: in vivo and in vitro studies of the aberrant transcription arising from two novel splice-site variants in SLC25A13.
This study aimed to characterize the pathogenicity of 2 novel splice-site variants ofSLC25A13 gene. Two patients (C0476 and C0556) suspected to have NICCD, their family members and 9 healthy volunteers were recruited as the research subjects. The SLC25A13 genotypes NG_012247.2(NM_014251.3): c.[852_855del];[69+5G>A] in patient C0476 and c.[1453-1G>A]; [1751-5_1751-4ins(2684)] in patient C0556 were identified by means of polymerase chain reaction, long and accurate polymerase chain reaction, as well as Sanger sequencing. The 2 splice-site variants were absent in control databases and predicted to be pathogenic by compu...
Source: European Journal of Medical Genetics - January 23, 2021 Category: Genetics & Stem Cells Authors: Lin WX, Deng LJ, Liu R, Qiu JW, Cheng Y, Zhang ZH, Chen FP, Song YZ Tags: Eur J Med Genet Source Type: research

Recurrent necrotizing cellulitis, multi-organ autoimmune disease and humoral immunodeficiency due to a novel NFKB1 frameshift mutation.
CONCLUSION: This is the first case of a patient with recurrent necrotizing cellulitis and immune mediated multi-organ involvement (heart, lungs, intestine) carrying the novel frameshift mutation c.2671del (p.Ala891Glnfs*6) in NFKB1 effectively treated with IVIG, low-dose corticosteroids and methotrexate. PMID: 33486103 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - January 21, 2021 Category: Genetics & Stem Cells Authors: Bergbreiter A, Jaeger T, Karle A, Bitzinger D, Ettl T, Spanier G, Jägle H, Neu R, Söder Y, Evert M, Reichert TE, Berneburg M, Brochhausen C, Schreml J, Fliegauf M, Salzer U, Redel A, Schreml S Tags: Eur J Med Genet Source Type: research

First Evidence of Involvement of TBC1D25 in Causing Human Male Infertility.
Abstract Male infertility is a heterogeneous disorder which may result from disruption in molecular and cellular pathways involved in spermatogenesis. Several reports have described abnormal spermatogenesis because of defective autophagy in model organisms. In the present study, we have clinically and genetically characterized a family segregating oligozoospermia in X-linked pattern. Exome sequencing revealed a disease-causing missense variant [NM_002536, c.149A>C, p.(Glu50Ala)] in TBC1D25, an autophagy gene located on human chromosome Xp11.23. In view of broad expression of the gene in testes and effect of the...
Source: European Journal of Medical Genetics - January 15, 2021 Category: Genetics & Stem Cells Authors: Nawaz S, Hussain S, Basit S, Ahmad W Tags: Eur J Med Genet Source Type: research

Homozygosity for the pathogenic RET hotspot variant p.Cys634Trp: A consanguineous family with MEN2A.
We present the first report of individuals homozygous for the highly activating RET p.Cys634Trp pathogenic variant and discuss disease severity and onset in this rare occurrence. PMID: 33450337 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - January 12, 2021 Category: Genetics & Stem Cells Authors: Schirwani S, Fraser S, Mushtaq T, Chengot P, Mavrogiannis LA, Jewell R, Adlard J Tags: Eur J Med Genet Source Type: research

Homozygous n.64C > T mutation in mitochondrial RNA-processing endoribonuclease gene causes Cartilage Hair Hypoplasia Syndrome in two siblings.
We describe the prenatal and postnatal growth pattern of the two affected patients, showing severe pre- and post-natal growth deficiency. PMID: 33444820 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - January 11, 2021 Category: Genetics & Stem Cells Authors: Licia L, Silvia C, Emma B, Laura L, Olga C, Simona M, Alberto B, Lorenzo I Tags: Eur J Med Genet Source Type: research

Clinical and genetic evaluation of Danish patients with pycnodysostosis.
CONCLUSION: This study provides information about genotypes and phenotypes in a Danish pycnodysostosis population. It reports new data about the complications such as bone fractures and it elucidates the levels of bone turnover markers as well as the density of the bones in one of the biggest cohort of pycnodysostosis patients ever published. An individualised approach to treatment in this patient group is necessary as the phenotype including complications varies between patients. Additional studies are needed to further understand genotype-phenotype correlations. PMID: 33429075 [PubMed - as supplied by publisher] (So...
Source: European Journal of Medical Genetics - January 8, 2021 Category: Genetics & Stem Cells Authors: Doherty MA, Langdahl BL, Vogel Denmark I, Haagerup A Tags: Eur J Med Genet Source Type: research

Mandibuloacral Dysplasia Type A in Five Tunisian Patients.
We report five Tunisian patients harboring the same homozygous c.1580G> A; p. (Arg527His) mutation in LMNA gene. The patients presented with typical features of mandibuloacral dysplasia including, prominent eyes, thin or beaked nose, dental overcrowding, mandibular hypoplasia, short and broad finger's distal phalanges with round tips and lipodystrophy type A. Newly recognized signs are growth hormone deficiency and dilated cardiomyopathy. Genotype-phenotype correlation found that at least one of the disease's LMNA mutant alleles involve one of the highly conserved aminoacids, residing in a key site domain for protein fu...
Source: European Journal of Medical Genetics - January 7, 2021 Category: Genetics & Stem Cells Authors: R S, H M, M T, A A, M G, I H, E K, K M, F M, R M Tags: Eur J Med Genet Source Type: research

Novel mutations in Uridyl-diphosphate-Glucuronosyl-Transferase 1A1 (UGT1A1) gene in Tunisian patients with unconjugated hyperbilirubinemia.
CONCLUSION: Our study provides novel data on UCB among Tunisians. Furthermore, we report four novel mutations associated with both GS and CNS. The identification of these mutations increases the spectrum of the UGT1A1 mutations and contributes to an understanding of the molecular abnormalities associated with unconjugated hyperbilirubinemia. PMID: 33421605 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - January 6, 2021 Category: Genetics & Stem Cells Authors: Trabelsi N, Chaouch L, Haddad F, Jaouani M, Barkaoui E, Darragi I, Chaouachi D, Boudrigua I, Menif S, Abbes S Tags: Eur J Med Genet Source Type: research

Familial Beckwith-Wiedemann Syndrome: prenatal manifestation and a possible expansion of the phenotype.
We describe a case of Beckwith-Wiedemann syndrome (BWS) demonstrating pre- and post-natal intra-familial variability. Our first encounter with the family occurred in the 1990s following the birth of 3 affected offspring. The first two pregnancies presented with exomphalos and elevated second trimester maternal serum alpha-fetoprotein (msAFP, 3.43 and 4.01 MOM, respectively) as well as elevated maternal human chorionic gonadotrophin (mhCG, 4.33 and 8.8 MOM, respectively). The diagnosis of BWS was confirmed postnatally in both cases. The third ongoing pregnancy presented only with elevated mhCG (7.09 MOM) and no malformation...
Source: European Journal of Medical Genetics - January 6, 2021 Category: Genetics & Stem Cells Authors: Brabbing-Goldstein D, Yaron Y, Reches A Tags: Eur J Med Genet Source Type: research

Broad neurodevelopmental features and cortical anomalies associated with a novel de novo KMT2A variant in Wiedemann-Steiner syndrome.
Abstract Wiedemann-Steiner syndrome (WDSTS) is a rare genetic disorder including developmental delay/intellectual disability (DD/ID), hypertrichosis cubiti, short stature, and distinctive facial features, caused by mutation in KMT2A gene, which encodes a histone methyltransferase (H3K4) that regulates chromatin-mediated transcription. Different neurodevelopmental phenotypes have been described within the WDSTS spectrum, including a peculiar Autism Spectrum Disorder (ASDs) subtype in some affected individuals. Here, we report a 9-year-old Caucasian male found by next-generation panel sequencing to carry a novel het...
Source: European Journal of Medical Genetics - December 30, 2020 Category: Genetics & Stem Cells Authors: Nardello R, Mangano GD, Fontana A, Gagliardo C, Midiri F, Borgia P, Brighina F, Raieli V, Mangano S, Salpietro V Tags: Eur J Med Genet Source Type: research

De novo DNM1L variant presenting with severe muscular atrophy, dystonia and sensory neuropathy.
Abstract DNM1L encodes dynamin-related protein 1 (DRP1), a multi-domain GTPase essential for mitochondrial and peroxisomal division. Autosomal dominant and recessive variants in DNM1L cause encephalopathy due to defective mitochondrial and peroxisomal fission 1 (EMPF1), which presents as a complex and clinically heterogeneous neurological disorder of variable severity, often accompanied by seizures. Clinical features are diverse, and no clear phenotype-genotype correlations were drawn to date. DNM1L-related sensory neuropathy has recently been reported as a predominant feature in one case with a de novo variant in...
Source: European Journal of Medical Genetics - December 30, 2020 Category: Genetics & Stem Cells Authors: Keller N, Paketci C, Edem P, Thiele H, Yis U, Wirth B, Karakaya M Tags: Eur J Med Genet Source Type: research

Brothers with novel compound heterozygous mutations in COL27A1 causing dental and genital abnormalities.
In this study, we identified novel COL27A1 compound heterozygous variants in two brothers with rhizomelia and congenital hip dislocation as well as dental and genital abnormalities that have not yet been reported in Steel syndrome. This variant, of maternal origin, caused an amino acid substitution of arginine for glycine, c.2026G>C or p.G676R, in the collagen helix domain, which is assumed to damage the structure of the helix. The paternally transmitted variant, c.2367G>A, is located at the 3' end of exon 12, and cDNA analysis revealed a splicing alteration. These novel, compound heterozygous COL27A1 variants might ...
Source: European Journal of Medical Genetics - December 25, 2020 Category: Genetics & Stem Cells Authors: Satoh C, Kondoh T, Shimizu H, Kinoshita A, Mishima H, Nishimura G, Miyazaki M, Okano K, Kumai Y, Yoshiura KI Tags: Eur J Med Genet Source Type: research

Biallelic variants in ETV2 in a family with congenital heart defects, vertebral abnormalities and preaxial polydactyly.
We describe a family in which four consecutive pregnancies were characterized by the combination of fetal congenital heart malformations and vertebral anomalies. In addition, preaxial polydactyly was detected in one of the fetuses. Reanalysis of the non-diagnostic clinical exome data revealed compound heterozygous variants c.350del, p.(Gly117AlafsTer90) and c.757G>T, p.(Asp253Tyr) in ETV2 which have previously not been known to be associated with a phenotype in humans. In mice, Etv2 encodes an obligatory transcription factor involved in the generation of hematopoietic and endothelial cells. Its homozygous disruption res...
Source: European Journal of Medical Genetics - December 21, 2020 Category: Genetics & Stem Cells Authors: Basel-Salmon L, Ruhrman-Shahar N, Barel O, Hagari O, Marek-Yagel D, Azulai N, Bazak L, Svirsky R, Reznik-Wolf H, Lidzbarsky GA, Shohat M Tags: Eur J Med Genet Source Type: research

Early-onset parkinsonism in PPP2R5D-related neurodevelopmental disorder.
Abstract PPP2R5D-related neurodevelopmental disorder (NDD) is a rare autosomal-dominant disease with developmental delay and mild to severe intellectual disability. So far, fewer than 30 affected individuals with mostly recurrent, de novo missense variants in PPP2R5D were reported. Recently, parkinsonism with an onset between 20 and 40 years was reported in four adult individuals with the same p.(Glu200Lys) variant in PPP2R5D. By trio exome sequencing we now identified the variant p.(Glu198Lys) in a 29 year old woman presenting with typical clinical manifestations of PPP2R5D-related neurodevelopmental disorder and...
Source: European Journal of Medical Genetics - December 15, 2020 Category: Genetics & Stem Cells Authors: Hetzelt KLML, Kerling F, Kraus C, Rauch C, Thiel CT, Winterholler M, Reis A, Zweier C Tags: Eur J Med Genet Source Type: research

Dilated cardiomyopathy in a patient with autosomal dominant EEF1A2-related neurodevelopmental disorder.
This report describes a nine-year-old female patient who presented with neurodevelopmental phenotypes and dilated cardiomyopathy. Analysis of 193 epilepsy genes by focused exome sequencing revealed a novel heterozygous variant c.46G>C (p.Val16Leu; NM_001958.3) in EEF1A2. The variant was not detected in either parent, confirming its de novo origin. No additional variants that explain the patient's phenotypes were found by subsequent whole exome analysis. Copy number analysis of the exome data and exon-level microarray excluded a deletion in the other allele of EEF1A2. We present the first patient with a heterozygous path...
Source: European Journal of Medical Genetics - December 8, 2020 Category: Genetics & Stem Cells Authors: Kaneko M, Rosser T, Raca G Tags: Eur J Med Genet Source Type: research

Milder presentation of TELO2-related syndrome in two sisters homozygous for the p.Arg609His pathogenic variant.
We describe the case of two sisters, carrying the homozygous p.Arg609His variant of the gene, who present a milder phenotype of TELO2-related syndrome. Such variant has been reported once in a more severely affected patient, in compound heterozygous state associated with the p.Pro260Leu variant, suggesting a possible role of the p.Arg609His variant in determining milder phenotypes. Comparing the siblings with all previously reported cases, we offer an overview on the condition and discuss TELO2 genetic interactions, in order to further explore the molecular bases of this recently described disorder. PMID: 33307281 [Pu...
Source: European Journal of Medical Genetics - December 8, 2020 Category: Genetics & Stem Cells Authors: Ciaccio C, Duga V, Pantaleoni C, Esposito S, Moroni I, Pinelli M, Castello R, Nigro V, Chiapparini L, D'Arrigo S, TUDP Study Group Tags: Eur J Med Genet Source Type: research

Genetic Essentialism: The Mediating Role of Essentialist Biases on the Relationship between Genetic Knowledge and the Interpretations of Genetic Information.
CONCLUSION: GET seem to predict unwarranted effects of exposure to news headlines about genetic science, whereas GK seems to indirectly mitigate the same unwarranted effects. PMID: 33285312 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - December 4, 2020 Category: Genetics & Stem Cells Authors: Dar-Nimrod I, Kuntzman R, MacNevin G, Lynch K, Woods M, Morandini J Tags: Eur J Med Genet Source Type: research

Deep intronic TIMMDC1 variant delays diagnosis of rapidly progressive complex I deficiency.
This report illustrates the importance of considering mitochondrial disease even when laboratory findings are normal, and the added value of targeted sequencing of introns. PMID: 33278652 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - December 2, 2020 Category: Genetics & Stem Cells Authors: Naber M, Hellebrekers D, Nievelstein RAJ, van Hasselt PM, van Jaarsveld RH, Cuppen I, Oegema R Tags: Eur J Med Genet Source Type: research

Structural abnormalities of chromosome 8 and Fetoplacental Discrepancy: A second case report and review of fetal phenotype of 8p inverted duplication deletion syndrome.
We described a new second case of fetoplacental discrepancy involving first trimester prenatal detection of mosaic isochromosome i(8)(q10). A 32-year-old woman underwent chorionic villous sampling because of increased fetal nuchal translucency. Analysis of direct chromosome preparations was performed by R-banding and FISH using subtelomeric, centromeric and whole chromosome painting probes for chromosome 8 showing the presence of an isochromosome 8q with a complex, female mosaic karyotype: mos 46,XX,i(8)(q10)[13]/46,XX,del(8)(p23)[10]. Cytogenetic analysis of cultured CVS showed an interstitial duplication with concomitant...
Source: European Journal of Medical Genetics - November 25, 2020 Category: Genetics & Stem Cells Authors: Huynh MT, Riteau AS, Moradkhani K, Pichon O, Richard S, Joubert M, Bézieau S Tags: Eur J Med Genet Source Type: research

Expanding the spectrum of VAC14 related pediatric-onset neurological disease; striatonigral degeneration with brainstem involvement.
MD Abstract VAC14 related childhood-onset striatonigral degeneration was first defined in 2016 in two unrelated children with sudden onset neurological disease and regression of developmental milestones. Up to now, 11 cases have been reported. VAC14 is a component of a trimolecular complex that tightly regulates the level of phosphatidylinositol 3,5-bisphosphate (PI (3, 5)P2) and PI (3, 5)P2 is critical for the survival of neural cells. VAC14 pathogenic variants cause prominent vacuolation of neurons in basal ganglia of patients with childhood-onset striatonigral degeneration. Here, we present a patient with a ho...
Source: European Journal of Medical Genetics - November 25, 2020 Category: Genetics & Stem Cells Authors: Karaoğlu P, Köse MD Tags: Eur J Med Genet Source Type: research

Further expanding the clinical phenotype in Bainbridge-Ropers Syndrome and dissecting genotype-phenotype correlation in the ASXL3 mutational cluster regions.
Abstract Bainbridge-Ropers syndrome (BRPS) [OMIM#615485] is a neurodevelopmental disorder, characterized by delayed psychomotor development with generalized hypotonia, intellectual disability with poor or absent speech, feeding difficulties, growth failure, specific craniofacial and minor skeletal features. It was firstly reported in 2013 by Bainbridge et al., who observed a group of individuals sharing overlapping features with Bohring-Opitz syndrome which were caused by pathogenic variant in ASXL1, who indeed carried truncating mutations in ASXL3. To date, 33 cases were described in the literature. BRPS is cause...
Source: European Journal of Medical Genetics - November 23, 2020 Category: Genetics & Stem Cells Authors: Yu KP, Luk HM, Fung JLF, Chung BH, Lo IF Tags: Eur J Med Genet Source Type: research

Growth charts in Cockayne syndrome type 1 and type 2.
Abstract Cockayne syndrome (CS) is a multisystem degenerative disorder divided in 3 overlapping subtypes, with a continuous phenotypic spectrum : CS2 being the most severe form, CS1 the classical form and CS3 the late-onset form. Failure to thrive and growth difficulties are among the most consistent features of CS, leaving affected individuals vulnerable to numerous medical complications, including adverse effects of undernutrition, abrupt overhydration and overfeeding. There is thus a significant need for specific growth charts. We retrospectively collected growth parameters from genetically-confirmed CS1 and CS...
Source: European Journal of Medical Genetics - November 20, 2020 Category: Genetics & Stem Cells Authors: Baer S, Tuzin N, Kang PB, Mohammed S, Kubota M, van Ierland Y, Busa T, Rossi M, Morel G, Michot C, Baujat G, Durand M, Obringer C, Le May N, Calmels N, Laugel V Tags: Eur J Med Genet Source Type: research

Recurrent prenatal piezo1-related lymphatic dysplasia: expanding molecular and ultrasound findings.
We describe for the first time recurrent pregnancies showing different ultrasound presentations of lymphatic dysplasia. The first fetus displayed diffuse subcutaneous cysts and septations while the second one presented fetal hydrops. Exome sequencing results at 18 gestational weeks in the second pregnancy showed compound heterozygosity for two novel PIEZO1 variants, afterwards detected also in the first fetus and in the heterozygous parents. Both ultrasound and genetic findings expand the current knowledge of PIEZO1-related GLD. We suggest exome sequencing in hydropic fetuses with normal cytogenetics and in pregnancies wit...
Source: European Journal of Medical Genetics - November 20, 2020 Category: Genetics & Stem Cells Authors: Mastromoro G, Guadagnolo D, Giancotti A, Di Gregorio MG, Marchionni E, Vena F, Lepri FR, Bargiacchi L, Ventriglia F, Di Gioia C, Novelli A, Pizzuti A Tags: Eur J Med Genet Source Type: research

CDKL5 mutations may mimic Pitt-Hopkins syndrome phenotype.
to AM Abstract Genetic conditions comprise a wide spectrum of different phenotypes, rapidly expanding due to new diagnostic methodologies. Patients' facial features and clinical history represent the key elements leading clinicians to the right diagnosis. CDKL5-early onset epilepsy and Pitt-Hopkins syndrome are two well-known genetic conditions, with a defined phenotype sharing some common characteristics like early-onset epilepsy and hyperventilation episodes. Whilst facial features represent a diagnostic handle in patients with Pitt-Hopkins syndrome, clinical history is crucial in patients carrying a mutation in...
Source: European Journal of Medical Genetics - November 18, 2020 Category: Genetics & Stem Cells Authors: Currò A, Doddato G, Bruttini M, Zollino M, Marangi G, Zappella M, Renieri A, Pinto AM Tags: Eur J Med Genet Source Type: research

CHARGE Syndrome in the Era of Molecular Diagnosis: Similar Outcomes in those without Coloboma or Choanal Atresia.
We describe 18 individuals with CHD7-confirmed diagnosis from 15 families. The most sensitive finding in the cohort was temporal bone malformations, present in 13/15 individuals. Individuals had an average of 1.6 major features and 3.3 minor features defined by the Blake et al. guidelines. Despite lack of major features or major malformations, the majority of individuals continued to have difficulties with pneumonia, aspiration, secretion management and motility issues that greatly impacted their lives. Our findings illustrate the need for molecular testing and timely recognition given that the major co-morbidities are fre...
Source: European Journal of Medical Genetics - November 12, 2020 Category: Genetics & Stem Cells Authors: Simpson BN, Khattar D, Saal H, Prada C, Choo D, Marcheschi L, Wiley S, Hopkin RJ Tags: Eur J Med Genet Source Type: research

A novel NAPB splicing mutation identified by Trio-based exome sequencing is associated with early-onset epileptic encephalopathy.
Abstract N-ethylmaleimide-sensitive factor attachment proteins (NAP: NAPA and NAPB) play a role in Soluble N-ethylmaleimide-sensitive accessory protein receptor (SNARE) complex dissociation and recycling, associated with neuronal regulation and brain development and various severe early-onset epilepsies. Here, we report two patients from a Chinese family presenting with unexplained early-onset epileptic encephalopathies (EOEE) syndrome characterized by multifocal seizures, profound intellectual disability and global developmental delay. We identified the homozygous c.433-1G>A variant of the NAPB as the causativ...
Source: European Journal of Medical Genetics - November 12, 2020 Category: Genetics & Stem Cells Authors: Zhao X, Wang Y, Cai A, Mei S, Liu N, Kong X Tags: Eur J Med Genet Source Type: research

Low penetrance COL5A1 variants in a young patient with intracranial aneurysm and very mild signs of Ehlers-Danlos syndrome.
Abstract Spontaneous cervical artery dissection (CeAD) is a major cause of ischemic stroke in young adults, whose genetic susceptibility factors are still largely unknown. Nevertheless, subtle ultrastructural connective tissue alterations (especially in the collagen fibril morphology) are recognized in a large proportion of CeAD patients, in which recent genetic investigations reported an enrichment of variants in genes associated with known connective tissue disorders. In this regard, COL5A1 variants have been reported in a small subset of CeAD patients, with or without classical Ehlers-Danlos syndrome (cEDS) fea...
Source: European Journal of Medical Genetics - November 12, 2020 Category: Genetics & Stem Cells Authors: Errichiello E, Malara A, Grimod G, Avolio L, Balduini A, Zuffardi O Tags: Eur J Med Genet Source Type: research

Novel neuroclinical findings of autosomal recessive primary microcephaly 15 in a consanguineous Iranian family.
In this study, we describe an 11-year-old male who is affected by autosomal recessive primary microcephaly 15. This patient also shows severe intellectual disability, recurrent respiratory and renal infections, low birth weight, and developmental delay. After doing clinical and neuroimaging evaluations, due to heterogeneity of neurogenetic disorders, no narrow clinical diagnosis was possible, therefore, we utilized targeted-exome sequencing to identify any causative genetic factors. This revealed a homozygous in-frame deletion (NM_001136493.1: c.241_243del; p.(Val81del)) in the MFSD2A gene as the most likely disease-suscep...
Source: European Journal of Medical Genetics - November 11, 2020 Category: Genetics & Stem Cells Authors: Razmara E, Azimi H, Tavasoli AR, Fallahi E, Sheida SV, Eidi M, Bitaraf A, Farjami Z, Daneshmand MA, Garshasbi M Tags: Eur J Med Genet Source Type: research

Digestive involvement in a severe form of Snyder-Robinson syndrome: possible expansion of the phenotype.
Abstract Snyder-Robinson syndrome (OMIM #309583) is a rare X-linked condition, caused by mutation in the SMS gene (MIM *300105), characterized by a wide spectrum of clinical signs including developmental delay, epilepsy, asthenic habitus, dysmorphism, osteopenia, and renal or genital anomalies. Here we describe two maternal half-brothers who both presented with severe neurodevelopmental delay, seizures, hearing loss, facial dysmorphism, renal and ophthalmologic anomalies, failure to thrive and premature death. A novel p.(Gly203Asp) variant was found at the hemizygous state in the two boys, and an elevated Spermidi...
Source: European Journal of Medical Genetics - November 10, 2020 Category: Genetics & Stem Cells Authors: Dontaine P, Kottos E, Dassonville M, Balasel O, Catros V, Soblet J, Perlot P, Vilain C Tags: Eur J Med Genet Source Type: research

Utility of a mainstreamed genetic testing pathway in breast and ovarian cancer patients during the COVID-19 pandemic.
CONCLUSIONS: MGT guaranteed care continuity in BC/OC patients during the critical phases of the COVID-19 pandemic, with immediate implications for PV carriers. More broadly, we report for the first time the successful implementation of MGT in France. PMID: 33186762 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - November 10, 2020 Category: Genetics & Stem Cells Authors: Benusiglio PR, Korenbaum C, Vibert R, Ezenfis J, Geoffron S, Paul C, Richard S, Byrde V, Lejeune M, Guillerm E, Basset N, Lotz JP, Chabbert-Buffet N, Gligorov J, Coulet F Tags: Eur J Med Genet Source Type: research

Presymptomatic diagnosis of CYP24A1-related infantile idiopathic hypercalcemia: A case report.
In this study, we present a family with two daughters diagnosed with IIH due to two different mutations in CYP24A1 gene. Based on next-generation sequencing (NGS), the elder daughter was diagnosed as carrying the mutations CYP24A1: c.1186C > T; (p.Arg396Trp) and c.428_430del; (p.Glu143del). Within this context, we were able to presymptomatically diagnose her newborn sister using Sanger sequencing technique. Screening for CYP24A1 mutations in families with IIH history helps preventing disease manifestations in newborn siblings. Thus, NGS combined with Sanger sequencing validation opens up the perspective of pre...
Source: European Journal of Medical Genetics - November 10, 2020 Category: Genetics & Stem Cells Authors: Mirea AM, Pop RM, Căinap SS, Trifa AP Tags: Eur J Med Genet Source Type: research

Osteogenesis Imperfecta type I: the role of deep phenotyping in a patient with a ruptured uterus.
This report demonstrates the potential role for ultrastructural tissue examination and deep phenotyping, to allow further insights into the relationship between genotype and phenotype. PMID: 33166682 [PubMed - as supplied by publisher] (Source: European Journal of Medical Genetics)
Source: European Journal of Medical Genetics - November 6, 2020 Category: Genetics & Stem Cells Authors: Redman MG, Wagner BE, Balasubramanian M Tags: Eur J Med Genet Source Type: research