Publications by authors named "Nursel Elcioglu"

86 Publications

High prevalence of multilocus pathogenic variation in neurodevelopmental disorders in the Turkish population.

Am J Hum Genet 2021 Oct 28;108(10):1981-2005. Epub 2021 Sep 28.

Department of Medical Genetics, Adana City Training and Research Hospital, Adana 01170, Turkey.

Neurodevelopmental disorders (NDDs) are clinically and genetically heterogenous; many such disorders are secondary to perturbation in brain development and/or function. The prevalence of NDDs is > 3%, resulting in significant sociocultural and economic challenges to society. With recent advances in family-based genomics, rare-variant analyses, and further exploration of the Clan Genomics hypothesis, there has been a logarithmic explosion in neurogenetic "disease-associated genes" molecular etiology and biology of NDDs; however, the majority of NDDs remain molecularly undiagnosed. We applied genome-wide screening technologies, including exome sequencing (ES) and whole-genome sequencing (WGS), to identify the molecular etiology of 234 newly enrolled subjects and 20 previously unsolved Turkish NDD families. In 176 of the 234 studied families (75.2%), a plausible and genetically parsimonious molecular etiology was identified. Out of 176 solved families, deleterious variants were identified in 218 distinct genes, further documenting the enormous genetic heterogeneity and diverse perturbations in human biology underlying NDDs. We propose 86 candidate disease-trait-associated genes for an NDD phenotype. Importantly, on the basis of objective and internally established variant prioritization criteria, we identified 51 families (51/176 = 28.9%) with multilocus pathogenic variation (MPV), mostly driven by runs of homozygosity (ROHs) - reflecting genomic segments/haplotypes that are identical-by-descent. Furthermore, with the use of additional bioinformatic tools and expansion of ES to additional family members, we established a molecular diagnosis in 5 out of 20 families (25%) who remained undiagnosed in our previously studied NDD cohort emanating from Turkey.
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http://dx.doi.org/10.1016/j.ajhg.2021.08.009DOI Listing
October 2021

MFSD2A-associated primary microcephaly - Expanding the clinical and mutational spectrum of this ultra-rare disease.

Eur J Med Genet 2021 Oct 13;64(10):104310. Epub 2021 Aug 13.

Institute for Human Genetics, University Hospital Essen, Germany. Electronic address:

MFSD2A, a member of the major facilitator superfamily (MFS), is a transmembrane transporter responsible for the uptake of specific essential fatty acids through the blood-brain barrier (BBB) to the brain. The transporter is crucial for early embryonic brain development and a major factor in the formation and maintenance of the BBB. Mfsd2a-knockout mice show a leakage of the BBB in early embryonic stages and develop a phenotype characterized by microcephaly, cognitive impairment, and anxiety. So far, homozygous or compound heterozygous MFSD2A mutations in humans have only been reported in 13 different families with a total of 28 affected individuals. The phenotypical spectrum of patients with MFSD2A variants is rather broad but all patients present with microcephaly and severe intellectual disability, absent or limited speech, and walking difficulties. Severely affected patients develop seizures and show brain malformations and have, above all, a profound developmental delay hardly reaching any developmental motor milestones. Here, we report on two unrelated individuals with novel homozygous variants in the MFSD2A gene, presenting with severe primary microcephaly, brain malformations, profound developmental delay, and epilepsy, including hypsarrhythmia. Our findings extend the mutational spectrum of the bi-allelic MFSD2A variants causing autosomal recessive primary microcephaly type 15 and broaden the phenotypic spectrum associated with these pathogenic variants emphasizing the role of MFSD2A in early brain development.
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http://dx.doi.org/10.1016/j.ejmg.2021.104310DOI Listing
October 2021

Genome sequencing in families with congenital limb malformations.

Hum Genet 2021 Aug 22;140(8):1229-1239. Epub 2021 Jun 22.

Institute of Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.

The extensive clinical and genetic heterogeneity of congenital limb malformation calls for comprehensive genome-wide analysis of genetic variation. Genome sequencing (GS) has the potential to identify all genetic variants. Here we aim to determine the diagnostic potential of GS as a comprehensive one-test-for-all strategy in a cohort of undiagnosed patients with congenital limb malformations. We collected 69 cases (64 trios, 1 duo, 5 singletons) with congenital limb malformations with no molecular diagnosis after standard clinical genetic testing and performed genome sequencing. We also developed a framework to identify potential noncoding pathogenic variants. We identified likely pathogenic/disease-associated variants in 12 cases (17.4%) including four in known disease genes, and one repeat expansion in HOXD13. In three unrelated cases with ectrodactyly, we identified likely pathogenic variants in UBA2, establishing it as a novel disease gene. In addition, we found two complex structural variants (3%). We also identified likely causative variants in three novel high confidence candidate genes. We were not able to identify any noncoding variants. GS is a powerful strategy to identify all types of genomic variants associated with congenital limb malformation, including repeat expansions and complex structural variants missed by standard diagnostic approaches. In this cohort, no causative noncoding SNVs could be identified.
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http://dx.doi.org/10.1007/s00439-021-02295-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263393PMC
August 2021

A novel mutation in the gene: Diagnostic approach from relatively common skeletal dysplasias to an extremely rare Odontochondrodysplasia.

J Clin Res Pediatr Endocrinol 2021 Jun 11. Epub 2021 Jun 11.

Department of Pediatric Genetics, Marmara University Medical School, Istanbul, Turkey.

Odontochondrodysplasia (ODCD, OMIM #184260) is a quite rare non-lethal skeletal dysplasia characterized by involvement of the spine and metaphyseal regions of the long bones, pulmonary hypoplasia, short stature, joint hypermobility, and dentinogenesis imperfecta. ODCD is inherited in an autosomal recessive fashion with an unknown frequency caused by mutations of the thyroid hormone receptor interactor 11 gene (TRIP11; OMIM *604505). TRIP11 gene encodes the Golgi microtubule-associated protein 210 (GMAP-210), which is an indispensable protein for the function of the Golgi apparatus. Mutations of the TRIP11 gene also cause achondrogenesis type 1A (ACG1A). Null mutations of TRIP11 lead to ACG1A, also known as a lethal skeletal dysplasia, while hypomorphic mutations cause ODCD. Here we report a male child diagnosed as ODCD with a novel compound heterozygote mutation who presented with skeletal changes, short stature, dentinogenesis imperfecta, and facial dysmorphism resembling Achondroplasia (ACH) and Hypochondroplasia (HCH).
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http://dx.doi.org/10.4274/jcrpe.galenos.2021.2021.0099DOI Listing
June 2021

From cataract to syndrome diagnosis: Revaluation of Warburg-Micro syndrome Type 1 patients.

Am J Med Genet A 2021 08 5;185(8):2325-2334. Epub 2021 May 5.

Department of Medical Genetics, Pamukkale University, Denizli, Turkey.

Warburg-Micro syndrome (WARBM) is a rare autosomal recessively inherited neuro-ophthalmologic syndrome. Although WARBM shows genetic heterogeneity, the pathogenic variants in RAB3GAP1 were the most common cause of WARBM. In this study, we aimed to evaluate the detailed clinical and dysmorphic features of seven WARBM1 patients and overview the variant spectrum of RAB3GAP1 in comparison with the literature who were referred due to congenital cataracts. A previously reported homozygous variant (c.2187_2188delGAinsCT) was identified in three of these patients, while the other four had three novel variants (c.251_258delAGAA, c.2606+1G>A, and c.2861_2862dupGC). Congenital cataract and corpus callosum hypo/agenesia are pathognomonic for WARBM, which could be distinguished from other similar syndromes with additional typical dysmorphic facial features. Although there is no known phenotype and genotype correlation in any type of WARBM, RAB3GAP1 gene analysis should be previously requested as the first step of genetic diagnosis in clinically suspicious patients when it is not possible to request a multi-gene panel.
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http://dx.doi.org/10.1002/ajmg.a.62234DOI Listing
August 2021

Disentangling molecular and clinical stratification patterns in beta-galactosidase deficiency.

J Med Genet 2021 Mar 18. Epub 2021 Mar 18.

Department of Pediatric Metabolism, Reference Center of Inherited Metabolic Disorders, Femme Mère Enfant Hospital, Lyon, France.

Introduction: This study aims to define the phenotypic and molecular spectrum of the two clinical forms of β-galactosidase (β-GAL) deficiency, GM1-gangliosidosis and mucopolysaccharidosis IVB (Morquio disease type B, MPSIVB).

Methods: Clinical and genetic data of 52 probands, 47 patients with GM1-gangliosidosis and 5 patients with MPSIVB were analysed.

Results: The clinical presentations in patients with GM1-gangliosidosis are consistent with a phenotypic continuum ranging from a severe antenatal form with hydrops fetalis to an adult form with an extrapyramidal syndrome. Molecular studies evidenced 47 variants located throughout the sequence of the gene, in all exons except 7, 11 and 12. Eighteen novel variants (15 substitutions and 3 deletions) were identified. Several variants were linked specifically to early-onset GM1-gangliosidosis, late-onset GM1-gangliosidosis or MPSIVB phenotypes. This integrative molecular and clinical stratification suggests a variant-driven patient assignment to a given clinical and severity group.

Conclusion: This study reports one of the largest series of b-GAL deficiency with an integrative patient stratification combining molecular and clinical features. This work contributes to expand the community knowledge regarding the molecular and clinical landscapes of b-GAL deficiency for a better patient management.
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http://dx.doi.org/10.1136/jmedgenet-2020-107510DOI Listing
March 2021

The genomic and clinical landscape of fetal akinesia.

Genet Med 2020 03 4;22(3):511-523. Epub 2019 Nov 4.

University of Cologne, University Hospital Cologne, Institute of Human Genetics, Cologne, Germany.

Purpose: Fetal akinesia has multiple clinical subtypes with over 160 gene associations, but the genetic etiology is not yet completely understood.

Methods: In this study, 51 patients from 47 unrelated families were analyzed using next-generation sequencing (NGS) techniques aiming to decipher the genomic landscape of fetal akinesia (FA).

Results: We have identified likely pathogenic gene variants in 37 cases and report 41 novel variants. Additionally, we report putative pathogenic variants in eight cases including nine novel variants. Our work identified 14 novel disease-gene associations for fetal akinesia: ADSSL1, ASAH1, ASPM, ATP2B3, EARS2, FBLN1, PRG4, PRICKLE1, ROR2, SETBP1, SCN5A, SCN8A, and ZEB2. Furthermore, a sibling pair harbored a homozygous copy-number variant in TNNT1, an ultrarare congenital myopathy gene that has been linked to arthrogryposis via Gene Ontology analysis.

Conclusion: Our analysis indicates that genetic defects leading to primary skeletal muscle diseases might have been underdiagnosed, especially pathogenic variants in RYR1. We discuss three novel putative fetal akinesia genes: GCN1, IQSEC3 and RYR3. Of those, IQSEC3, and RYR3 had been proposed as neuromuscular disease-associated genes recently, and our findings endorse them as FA candidate genes. By combining NGS with deep clinical phenotyping, we achieved a 73% success rate of solved cases.
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http://dx.doi.org/10.1038/s41436-019-0680-1DOI Listing
March 2020

The Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance.

Am J Hum Genet 2019 07 20;105(1):132-150. Epub 2019 Jun 20.

Department of Physiotherapy and Rehabilitation, Hasan Kalyoncu University, School of Health Sciences, Gaziantep 27000, Turkey.

Arthrogryposis is a clinical finding that is present either as a feature of a neuromuscular condition or as part of a systemic disease in over 400 Mendelian conditions. The underlying molecular etiology remains largely unknown because of genetic and phenotypic heterogeneity. We applied exome sequencing (ES) in a cohort of 89 families with the clinical sign of arthrogryposis. Additional molecular techniques including array comparative genomic hybridization (aCGH) and Droplet Digital PCR (ddPCR) were performed on individuals who were found to have pathogenic copy number variants (CNVs) and mosaicism, respectively. A molecular diagnosis was established in 65.2% (58/89) of families. Eleven out of 58 families (19.0%) showed evidence for potential involvement of pathogenic variation at more than one locus, probably driven by absence of heterozygosity (AOH) burden due to identity-by-descent (IBD). RYR3, MYOM2, ERGIC1, SPTBN4, and ABCA7 represent genes, identified in two or more families, for which mutations are probably causative for arthrogryposis. We also provide evidence for the involvement of CNVs in the etiology of arthrogryposis and for the idea that both mono-allelic and bi-allelic variants in the same gene cause either similar or distinct syndromes. We were able to identify the molecular etiology in nine out of 20 families who underwent reanalysis. In summary, our data from family-based ES further delineate the molecular etiology of arthrogryposis, yielded several candidate disease-associated genes, and provide evidence for mutational burden in a biological pathway or network. Our study also highlights the importance of reanalysis of individuals with unsolved diagnoses in conjunction with sequencing extended family members.
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http://dx.doi.org/10.1016/j.ajhg.2019.05.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612529PMC
July 2019

Molecular characterization of a large group of Mucopolysaccharidosis type IIIC patients reveals the evolutionary history of the disease.

Hum Mutat 2019 08 22;40(8):1084-1100. Epub 2019 Jun 22.

Department of Biochemistry and Molecular Medicine, Université de Montréal, Montreal, Quebec, Canada.

Mucopolysaccharidosis type IIIC (MPSIIIC) is a severe, rare autosomal recessive disorder caused by variants in the heparan-α-glucosaminide N-acetyltransferase (HGSNAT) gene which result in lysosomal accumulation of heparan sulfate. We analyzed clinical presentation, molecular defects and their haplotype context in 78 (27 novel) MPSIIIC cases from 22 countries, the largest group studied so far. We describe for the first time disease-causing variants in the patients from Brazil, Algeria, Azerbaijan, and Iran, and extend their spectrum within Canada, Colombia, Turkey, and the USA. Six variants are novel: two missense, c.773A>T/p.N258I and c.1267G>T/p.G423W, a nonsense c.164T>A/p.L55*, a splice-site mutation c.494-1G>A/p.[P165_L187delinsQSCYVTQAGVRWHHLGSLQALPPGFTPFSYLSLLSSWNC,P165fs], a deletion c.1348delG/p.(D450fs) and an insertion c.1479dupA/p.(Leu494fs). The missense HGSNAT variants lacked lysosomal targeting, enzymatic activity, and likely the correct folding. The haplotype analysis identified founder mutations, p.N258I, c.525dupT, and p.L55* in the Brazilian state of Paraiba, c.493+1G>A in Eastern Canada/Quebec, p.A489E in the USA, p.R384* in Poland, p.R344C and p.S518F in the Netherlands and suggested that variants c.525dupT, c.372-2G>A, and c.234+1G>A present in cis with c.564-98T>C and c.710C>A rare single-nucleotide polymorphisms, have been introduced by Portuguese settlers in Brazil. Altogether, our results provide insights into the origin, migration roots and founder effects of HGSNAT disease-causing variants, and reveal the evolutionary history of MPSIIIC.
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http://dx.doi.org/10.1002/humu.23752DOI Listing
August 2019

TNFRSF11A-Associated Dysosteosclerosis: A Report of the Second Case and Characterization of the Phenotypic Spectrum.

J Bone Miner Res 2019 10 5;34(10):1873-1879. Epub 2019 Aug 5.

Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.

Dysosteosclerosis (DOS) is a distinct form of sclerosing bone disease characterized by irregular osteosclerosis and platyspondyly. DOS is genetically heterogeneous; however, only five cases with SLC29A3 mutations and a single case with a splice-site mutation of TNFRSF11A have been reported, and TNFRSF11A is also a causal gene for osteopetrosis, autosomal recessive 7 (OP-AR7). Thus, the causal genes of DOS and their genotype-phenotype associations remain unclear. In this study, we examined a Japanese patient with DOS and found a novel variant in TNFRSF11A. The homozygous variant was a G to T transversion at the first nucleotide of exon 9 (c.784G>T). Although the variant was predicted to cause a stop codon mutation (p.E262*), in silico evaluation of the exonic splicing elements followed by RT-PCR for the patient-derived cells showed that it caused aberrant splicing due to the change in the exonic splicing element and produced two types of aberrant transcripts: One caused a premature stop codon (p.E262Vfs*17) leading to nonsense mutation-mediated mRNA decay; the other produced a protein with interstitial deletion (p.E262_Q279del). The effects of the mutation on five splicing isoforms of TNFRSF11A were different from those in OP-AR7, but comparable with those in the first DOS with the TNFRSF11A mutation. Thus, we identified the second case of DOS caused by the TNFRSF11A splice-site mutation and confirmed the novel disease entity. © 2019 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3805DOI Listing
October 2019

Ptosis as a unique hallmark for autosomal recessive WNT1-associated osteogenesis imperfecta.

Am J Med Genet A 2019 06 21;179(6):908-914. Epub 2019 Mar 21.

Department of Biomolecular Medicine, Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium.

Osteogenesis imperfecta (OI) is a heritable connective tissue disorder, mainly characterized by bone fragility and low bone mass. Defects in the type I procollagen-encoding genes account for the majority of OI, but increasingly more rare autosomal recessive (AR) forms are being identified, which are caused by defects in genes involved in collagen metabolism, bone mineralization, or osteoblast differentiation. Bi-allelic mutations in WNT1 have been associated with a rare form of AR OI, characterized by severe osteoporosis, vertebral compression, scoliosis, fractures, short stature, and variable neurological problems. Heterozygous WNT1 mutations have been linked to autosomal dominant early-onset osteoporosis. In this study, we describe the clinical and molecular findings in 10 new patients with AR WNT1-related OI. Thorough revision of the clinical symptoms of these 10 novel patients and previously published AR WNT1 OI cases highlight ptosis as a unique hallmark in the diagnosis of this OI subtype.
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http://dx.doi.org/10.1002/ajmg.a.61119DOI Listing
June 2019

Correction: The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin-Siris syndrome.

Genet Med 2019 Sep;21(9):2160-2161

University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.

The original version of this Article contained an error in the spelling of the author Pleuntje J. van der Sluijs, which was incorrectly given as Eline (P. J.) van der Sluijs. This has now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41436-018-0368-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752317PMC
September 2019

The oculoauriculofrontonasal syndrome: Further clinical characterization and additional evidence suggesting a nontraditional mode of inheritance.

Am J Med Genet A 2018 12 10;176(12):2740-2750. Epub 2018 Dec 10.

Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Interrégion Est, Centre Hospitalier Universitaire Dijon, Dijon, France.

The oculoauriculofrontonasal syndrome (OAFNS) is a rare disorder characterized by the association of frontonasal dysplasia (widely spaced eyes, facial cleft, and nose abnormalities) and oculo-auriculo-vertebral spectrum (OAVS)-associated features, such as preauricular ear tags, ear dysplasia, mandibular asymmetry, epibulbar dermoids, eyelid coloboma, and costovertebral anomalies. The etiology is unknown so far. This work aimed to identify molecular bases for the OAFNS. Among a cohort of 130 patients with frontonasal dysplasia, accurate phenotyping identified 18 individuals with OAFNS. We describe their clinical spectrum, including the report of new features (micro/anophtalmia, cataract, thyroid agenesis, polymicrogyria, olfactory bulb hypoplasia, and mandibular cleft), and emphasize the high frequency of nasal polyps in OAFNS (56%). We report the negative results of ALX1, ALX3, and ALX4 genes sequencing and next-generation sequencing strategy performed on blood-derived DNA from respectively, four and four individuals. Exome sequencing was performed in four individuals, genome sequencing in one patient with negative exome sequencing result. Based on the data from this series and the literature, diverse hypotheses can be raised regarding the etiology of OAFNS: mosaic mutation, epigenetic anomaly, oligogenism, or nongenetic cause. In conclusion, this series represents further clinical delineation work of the rare OAFNS, and paves the way toward the identification of the causing mechanism.
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http://dx.doi.org/10.1002/ajmg.a.40662DOI Listing
December 2018

Does the clinical phenotype of mucolipidosis-IIIγ differ from its αβ counterpart?: supporting facts in a cohort of 18 patients.

Clin Dysmorphol 2019 Jan;28(1):7-16

Greenwood Genetic Center, Greenwood, South Carolina.

Mucolipidosis-IIIγ (ML-IIIγ) is a recessively inherited slowly progressive skeletal dysplasia caused by mutations in GNPTG. We report the genetic and clinical findings in the largest cohort with ML-IIIγ so far: 18 affected individuals from 12 families including 12 patients from India, five from Turkey, and one from the USA. With consanguinity confirmed in eight of 12 families, molecular characterization showed that all affected patients had homozygous pathogenic GNPTG genotypes, underscoring the rarity of the disorder. Unlike ML-IIIαβ, which present with a broader spectrum of severity, the ML-III γ phenotype is milder, with onset in early school age, but nonetheless thus far considered phenotypically not differentiable from ML-IIIαβ. Evaluation of this cohort has yielded phenotypic findings including hypertrophy of the forearms and restricted supination as clues for ML-IIIγ, facilitating an earlier correct choice of genotype screening. Early identification of this disorder may help in offering a timely intervention for the relief of carpal tunnel syndrome, monitoring and surgery for cardiac valve involvement, and evaluation of the need for joint replacement. As this condition may be confused with rheumatoid arthritis, confirmation of diagnosis will prevent inappropriate use of immunosuppressants and disease-modifying agents.
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http://dx.doi.org/10.1097/MCD.0000000000000249DOI Listing
January 2019

Identification of candidate gene FAM183A and novel pathogenic variants in known genes: High genetic heterogeneity for autosomal recessive intellectual disability.

PLoS One 2018 30;13(11):e0208324. Epub 2018 Nov 30.

John P. Hussmann Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, United States of America.

The etiology of intellectual disability (ID) is heterogeneous including a variety of genetic and environmental causes. Historically, most research has not focused on autosomal recessive ID (ARID), which is a significant cause of ID, particularly in areas where parental consanguinity is common. Identification of genetic causes allows for precision diagnosis and improved genetic counseling. We performed whole exome sequencing to 21 Turkish families, seven multiplex and 14 simplex, with nonsyndromic ID. Based on the presence of multiple affected siblings born to unaffected parents and/or shared ancestry, we consider all families as ARID. We revealed the underlying causative variants in seven families in MCPH1 (c.427dupA, p.T143Nfs*5), WDR62 (c.3406C>T, p.R1136*), ASPM (c.5219_5225delGAGGATA, p.R1740Tfs*7), RARS (c.1588A>G, p.T530A), CC2D1A (c.811delG, p.A271Pfs*30), TUSC3 (c.793C>T, p.Q265*) and ZNF335 (c.808C>T, p.R270C and c.3715C>A, p.Q1239K) previously linked with ARID. Besides ARID genes, in one family, affected male siblings were hemizygous for PQBP1 (c.459_462delAGAG, p.R153Sfs*41) and in one family the proband was female and heterozygous for X-chromosomal SLC9A6 (c.1631+1G>A) variant. Each of these variants, except for those in MCPH1 and PQBP1, have not been previously published. Additionally in one family, two affected children were homozygous for the c.377G>A (p.W126*) variant in the FAM183A, a gene not previously associated with ARID. No causative variants were found in the remaining 11 families. A wide variety of variants explain half of families with ARID. FAM183A is a promising novel candidate gene for ARID.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0208324PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6267965PMC
May 2019

The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin-Siris syndrome.

Genet Med 2019 06 8;21(6):1295-1307. Epub 2018 Nov 8.

University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.

Purpose: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin-Siris patients (ARID1B-CSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting.

Methods: Clinicians entered clinical data in an extensive web-based survey.

Results: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified.

Conclusion: There are only minor differences between ARID1B-ID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features.
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http://dx.doi.org/10.1038/s41436-018-0330-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752273PMC
June 2019

Mutations in TOP3A Cause a Bloom Syndrome-like Disorder.

Am J Hum Genet 2018 08 26;103(2):221-231. Epub 2018 Jul 26.

Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany.

Bloom syndrome, caused by biallelic mutations in BLM, is characterized by prenatal-onset growth deficiency, short stature, an erythematous photosensitive malar rash, and increased cancer predisposition. Diagnostically, a hallmark feature is the presence of increased sister chromatid exchanges (SCEs) on cytogenetic testing. Here, we describe biallelic mutations in TOP3A in ten individuals with prenatal-onset growth restriction and microcephaly. TOP3A encodes topoisomerase III alpha (TopIIIα), which binds to BLM as part of the BTRR complex, and promotes dissolution of double Holliday junctions arising during homologous recombination. We also identify a homozygous truncating variant in RMI1, which encodes another component of the BTRR complex, in two individuals with microcephalic dwarfism. The TOP3A mutations substantially reduce cellular levels of TopIIIα, and consequently subjects' cells demonstrate elevated rates of SCE. Unresolved DNA recombination and/or replication intermediates persist into mitosis, leading to chromosome segregation defects and genome instability that most likely explain the growth restriction seen in these subjects and in Bloom syndrome. Clinical features of mitochondrial dysfunction are evident in several individuals with biallelic TOP3A mutations, consistent with the recently reported additional function of TopIIIα in mitochondrial DNA decatenation. In summary, our findings establish TOP3A mutations as an additional cause of prenatal-onset short stature with increased cytogenetic SCEs and implicate the decatenation activity of the BTRR complex in their pathogenesis.
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http://dx.doi.org/10.1016/j.ajhg.2018.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6080766PMC
August 2018

Further delineation of Malan syndrome.

Hum Mutat 2018 09 25;39(9):1226-1237. Epub 2018 Jun 25.

Belfast HSC Trust, Northern Ireland Regional Genetics Service, Belfast, Northern Ireland.

Malan syndrome is an overgrowth disorder described in a limited number of individuals. We aim to delineate the entity by studying a large group of affected individuals. We gathered data on 45 affected individuals with a molecularly confirmed diagnosis through an international collaboration and compared data to the 35 previously reported individuals. Results indicate that height is > 2 SDS in infancy and childhood but in only half of affected adults. Cardinal facial characteristics include long, triangular face, macrocephaly, prominent forehead, everted lower lip, and prominent chin. Intellectual disability is universally present, behaviorally anxiety is characteristic. Malan syndrome is caused by deletions or point mutations of NFIX clustered mostly in exon 2. There is no genotype-phenotype correlation except for an increased risk for epilepsy with 19p13.2 microdeletions. Variants arose de novo, except in one family in which mother was mosaic. Variants causing Malan and Marshall-Smith syndrome can be discerned by differences in the site of stop codon formation. We conclude that Malan syndrome has a well recognizable phenotype that usually can be discerned easily from Marshall-Smith syndrome but rarely there is some overlap. Differentiation from Sotos and Weaver syndrome can be made by clinical evaluation only.
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http://dx.doi.org/10.1002/humu.23563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175110PMC
September 2018

Recessive MYF5 Mutations Cause External Ophthalmoplegia, Rib, and Vertebral Anomalies.

Am J Hum Genet 2018 07 7;103(1):115-124. Epub 2018 Jun 7.

Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of M.I.T. and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Department Ophthalmology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Ophthalmology, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

MYF5 is member of the Myc-like basic helix-loop-helix transcription factor family and, in cooperation with other myogenic regulatory factors MYOD and MYF5, is a key regulator of early stages of myogenesis. Here, we report three consanguineous families with biallelic homozygous loss-of-function mutations in MYF5 who define a clinical disorder characterized by congenital ophthalmoplegia with scoliosis and vertebral and rib anomalies. The clinical phenotype overlaps strikingly with that reported in several Myf5 knockout mouse models. Affected members of two families share a haploidentical region that contains a homozygous 10 bp frameshift mutation in exon 1 of MYF5 (c.23_32delAGTTCTCACC [p.Gln8Leufs86]) predicted to undergo nonsense-mediated decay. Affected members of the third family harbor a homozygous missense change in exon 1 of MYF5 (c.283C>T [p.Arg95Cys]). Using in vitro assays, we show that this missense mutation acts as a loss-of-function allele by impairing MYF5 DNA binding and nuclear localization. We performed whole-genome sequencing in one affected individual with the frameshift mutation and did not identify additional rare variants in the haploidentical region that might account for differences in severity among the families. These data support the direct role of MYF5 in rib, spine, and extraocular muscle formation in humans.
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http://dx.doi.org/10.1016/j.ajhg.2018.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035164PMC
July 2018

Insights into Mutation Effect in Three Poikiloderma with Neutropenia Patients by Transcript Analysis and Disease Evolution of Reported Patients with the Same Pathogenic Variants.

J Clin Immunol 2018 05 16;38(4):494-502. Epub 2018 May 16.

Laboratorio di Citogenetica Medica e Genetica Molecolare, Centro di Ricerche e Tecnologie Biomediche IRCCS-Istituto Auxologico Italiano, Via Ariosto 13, 20145, Milan, Italy.

Purpose: Poikiloderma with neutropenia (PN) is a genodermatosis currently described in 77 patients, all presenting with early-onset poikiloderma, neutropenia, and several additional signs. Biallelic loss-of-function mutations in USB1 gene are detected in all molecularly tested patients but genotype-phenotype correlation remains elusive. Cancer predisposition is recognized among PN features and pathogenic variants found in patients who developed early in life myelodysplasia (n = 12), acute myeloid leukemia (n = 2), and squamous cell carcinoma (n = 2) should be kept into account in management and follow-up of novel patients. This will hopefully allow achieving data clustered on specific mutations relevant to oncological surveillance of the carrier patients.

Methods: We describe the clinical features of three unreported PN patients and characterize their USB1 pathogenic variants by transcript analysis to get insights into the effect on the overall phenotype and disease evolution.

Results: A Turkish boy is homozygous for the c.531delA deletion, a recurrent mutation in Turkey; an adult Italian male is compound heterozygous for two nonsense mutations, c.243G>A and c.541C>T, while an Italian boy is homozygous for the splicing c.683_693+1del variant. The identified mutations have already been reported in PN patients who developed hematologic or skin cancer. Aberrant mRNAs of all four mutated alleles could be identified confirming that transcripts of USB1 main isoform either carrying stop codons or mis-spliced may at least partially escape nonsense-mediated decay.

Conclusions: Our study addresses the need of gathering insights on genotype-phenotype correlations in newly described PN patients, by transcript analysis and information on disease evolution of reported patients with the same pathogenic variants.
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http://dx.doi.org/10.1007/s10875-018-0508-9DOI Listing
May 2018

Rothmund-Thomson Syndrome: Insights from New Patients on the Genetic Variability Underpinning Clinical Presentation and Cancer Outcome.

Int J Mol Sci 2018 Apr 6;19(4). Epub 2018 Apr 6.

Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, 20149 Milan, Italy.

Biallelic mutations in gene, a caretaker of the genome, cause Rothmund-Thomson type-II syndrome (RTS-II) and confer increased cancer risk if they damage the helicase domain. We describe five families exemplifying clinical and allelic heterogeneity of RTS-II, and report the effect of pathogenic variants by predictions and transcripts analyses. Complete phenotype of patients #39 and #42 whose affected siblings developed osteosarcoma correlates with their c.[1048_1049del], c.[1878+32_1878+55del] and c.[1568G>C;1573delT], c.[3021_3022del] variants which damage the helicase domain. Literature survey highlights enrichment of these variants affecting the helicase domain in patients with cancer outcome raising the issue of strict oncological surveillance. Conversely, patients #29 and #19 have a mild phenotype and carry, respectively, the unreported homozygous c.3265G>T and c.3054A>G variants, both sparing the helicase domain. Finally, despite matching several criteria for RTS clinical diagnosis, patient #38 is heterozygous for c.2412_2414del; no pathogenic CNVs out of those evidenced by high-resolution CGH-array, emerged as contributors to her phenotype.
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http://dx.doi.org/10.3390/ijms19041103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5979380PMC
April 2018

Dysosteosclerosis is also caused by TNFRSF11A mutation.

J Hum Genet 2018 Jun 22;63(6):769-774. Epub 2018 Mar 22.

Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, 108-8639, Japan.

Dysosteosclerosis (DOS) is a form of sclerosing bone disease characterized by irregular osteosclerosis and platyspondyly. Its mode of inheritance is autosomal recessive. SLC29A3 mutations have been reported as the causal gene in two DOS families, however, genetic heterogeneity has been suggested. By whole-exome sequencing in a Turkish patient with DOS, we found a novel splice-site mutation in TNFRSF11A. TNFRSF11A mutations have previously been reported in two autosomal dominant diseases (osteolysis, familial expansile and Paget disease of bone 2, early-onset) and an autosomal recessive disease (osteopetrosis, autosomal recessive 7). The biallelic mutation, c.616+3A>G, identified in our study was located in the splice donor site of intron 6 of TNFRSF11A. Exon trapping assay indicated the mutation caused skipping of exon 6, which was predicted to induce a frame-shift and an early termination codon in all known alternative transcript variants of TNFRSF11A. The predicted effect of the mutation for the isoforms was different from those of the previously reported mutations, which could explain the difference of their phenotypes. Thus, our study identified the second disease gene for DOS. TNFRSF11A isoforms may have the different roles in skeletal development and metabolism.
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http://dx.doi.org/10.1038/s10038-018-0447-6DOI Listing
June 2018

Novel and recurrent and mutations in the Marshall-Stickler syndrome spectrum.

Hum Genome Var 2017 5;4:17040. Epub 2017 Oct 5.

Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.

Marshall-Stickler syndrome represents a spectrum of inherited connective tissue disorders affecting the ocular, auditory, and skeletal systems. The syndrome is caused by mutations in the , , , , and genes. In this study, we examined four Turkish families with Marshall-Stickler syndrome using whole-exome sequencing and identified one mutation and three mutations. Two of the mutations were novel. Our findings expand our knowledge of the mutational spectrum that causes Marshall-Stickler syndrome.
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http://dx.doi.org/10.1038/hgv.2017.40DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5628180PMC
October 2017

REST Final-Exon-Truncating Mutations Cause Hereditary Gingival Fibromatosis.

Am J Hum Genet 2017 Jul;101(1):149-156

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:

Hereditary gingival fibromatosis (HGF) is the most common genetic form of gingival fibromatosis that develops as a slowly progressive, benign, localized or generalized enlargement of keratinized gingiva. HGF is a genetically heterogeneous disorder and can be transmitted either as an autosomal-dominant or autosomal-recessive trait or appear sporadically. To date, four loci (2p22.1, 2p23.3-p22.3, 5q13-q22, and 11p15) have been mapped to autosomes and one gene (SOS1) has been associated with the HGF trait observed to segregate in a dominant inheritance pattern. Here we report 11 individuals with HGF from three unrelated families. Whole-exome sequencing (WES) revealed three different truncating mutations including two frameshifts and one nonsense variant in RE1-silencing transcription factor (REST) in the probands from all families and further genetic and genomic analyses confirmed the WES-identified findings. REST is a transcriptional repressor that is expressed throughout the body; it has different roles in different cellular contexts, such as oncogenic and tumor-suppressor functions and hematopoietic and cardiac differentiation. Here we show the consequences of germline final-exon-truncating mutations in REST for organismal development and the association with the HGF phenotype.
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http://dx.doi.org/10.1016/j.ajhg.2017.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501868PMC
July 2017

Clinico-molecular analysis of eleven patients with Hermansky-Pudlak type 5 syndrome, a mild form of HPS.

Pigment Cell Melanoma Res 2017 Jan 20;30(6):563-570. Epub 2017 Oct 20.

Service Génétique Médicale, CHU de Bordeaux, Bordeaux, France.

Hermansky-Pudlak syndrome (HPS), first described in 1959, is a rare form of syndromic oculocutaneous albinism associated with bleeding diathesis and in some cases pulmonary fibrosis and granulomatous colitis. All 10 HPS types are caused by defects in vesicle trafficking of lysosome-related organelles (LRO) proteins. The HPS5 protein associates with HPS3 and HPS6 to form the biogenesis of lysosome-related organelles complex-2 (BLOC-2). Here, we report the clinical and genetic data of 11 patients with HPS-5 analyzed in our laboratory. We report 11 new pathogenic variants. The 11 patients present with ocular features that are typical for albinism, with mild hypopigmentation, and with no other major complication, apart from a tendency to bleed. HPS-5 therefore appears as a mild form of HPS, which is often clinically undistinguishable from mild oculocutaneous or ocular forms of albinism. Molecular analysis is therefore required to establish the diagnosis of this mild HPS form, which has consequences in terms of prognosis and of clinical management of the patients.
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http://dx.doi.org/10.1111/pcmr.12608DOI Listing
January 2017

Novel EYA1 variants causing Branchio-oto-renal syndrome.

Int J Pediatr Otorhinolaryngol 2017 Jul 26;98:59-63. Epub 2017 Apr 26.

John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA; Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL, USA. Electronic address:

Introduction: Branchio-oto-renal (BOR) syndrome is an autosomal dominant genetic disorder characterized by second branchial arch anomalies, hearing impairment, and renal malformations. Pathogenic mutations have been discovered in several genes such as EYA1, SIX5, and SIX1. However, nearly half of those affected reveal no pathogenic variant by traditional genetic testing.

Methods And Materials: Whole Exome sequencing and/or Sanger sequencing performed in 10 unrelated families from Turkey, Iran, Ecuador, and USA with BOR syndrome in this study.

Results: We identified causative DNA variants in six families including novel c.525delT, c.979T > C, and c.1768delG and a previously reported c.1779A > T variants in EYA1. Two large heterozygous deletions involving EYA1 were detected in additional two families. Whole exome sequencing did not reveal a causative variant in the remaining four families.

Conclusions: A variety of DNA changes including large deletions underlie BOR syndrome in different populations, which can be detected with comprehensive genetic testing.
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http://dx.doi.org/10.1016/j.ijporl.2017.04.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5516569PMC
July 2017

Heterozygous HNRNPU variants cause early onset epilepsy and severe intellectual disability.

Hum Genet 2017 07 9;136(7):821-834. Epub 2017 Apr 9.

Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany.

Pathogenic variants in genes encoding subunits of the spliceosome are the cause of several human diseases, such as neurodegenerative diseases. The RNA splicing process is facilitated by the spliceosome, a large RNA-protein complex consisting of small nuclear ribonucleoproteins (snRNPs), and many other proteins, such as heterogeneous nuclear ribonucleoproteins (hnRNPs). The HNRNPU gene (OMIM *602869) encodes the heterogeneous nuclear ribonucleoprotein U, which plays a crucial role in mammalian development. HNRNPU is expressed in the fetal brain and adult heart, kidney, liver, brain, and cerebellum. Microdeletions in the 1q44 region encompassing HNRNPU have been described in patients with intellectual disability (ID) and other clinical features, such as seizures, corpus callosum abnormalities (CCA), and microcephaly. Recently, pathogenic HNRNPU variants were identified in large ID and epileptic encephalopathy cohorts. In this study, we provide detailed clinical information of five novels and review two of the previously published individuals with (likely) pathogenic de novo variants in the HNRNPU gene including three non-sense and two missense variants, one small intragenic deletion, and one duplication. The phenotype in individuals with variants in HNRNPU is characterized by early onset seizures (6/7), severe ID (6/6), severe speech impairment (6/6), hypotonia (6/7), and central nervous system (CNS) (5/6), cardiac (4/6), and renal abnormalities (3/4). In this study, we broaden the clinical and mutational HNRNPU-associated spectrum, and demonstrate that heterozygous HNRNPU variants cause epilepsy, severe ID with striking speech impairment and variable CNS, cardiac, and renal anomalies.
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http://dx.doi.org/10.1007/s00439-017-1795-6DOI Listing
July 2017
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