@article {968, title = {Evaluating systematic reanalysis of clinical genomic data in rare disease from single center experience and literature review.}, journal = {Mol Genet Genomic Med}, volume = {8}, year = {2020}, month = {2020 11}, pages = {e1508}, abstract = {

BACKGROUND: Our primary aim was to evaluate the systematic reanalysis of singleton exome sequencing (ES) data for unsolved cases referred for any indication. A secondary objective was to undertake a literature review of studies examining the reanalysis of genomic data from unsolved cases.

METHODS: We examined data from 58 unsolved cases referred between June 2016 and March 2017. First reanalysis at 4-13~months after the initial report considered genes newly associated with disease since the original analysis; second reanalysis at 9-18~months considered all disease-associated genes. At 25-34~months we reviewed all cases and the strategies which solved them.

RESULTS: Reanalysis of existing ES data alone at two timepoints did not yield new diagnoses. Over the same timeframe, 10 new diagnoses were obtained (17\%) from additional strategies, such as microarray detection of copy number variation, repeat sequencing to improve coverage, and trio sequencing. Twenty-seven peer-reviewed articles were identified on the literature review, with a median new diagnosis rate via reanalysis of 15\% and median reanalysis timeframe of 22~months.

CONCLUSION: Our findings suggest that an interval of greater than 18~months from the original report may be optimal for reanalysis. We also recommend a multi-faceted strategy for cases remaining unsolved after singleton ES.

}, issn = {2324-9269}, doi = {10.1002/mgg3.1508}, author = {Tan, Natalie B and Stapleton, Rachel and Stark, Zornitza and Delatycki, Martin B and Yeung, Alison and Hunter, Matthew F and Amor, David J and Brown, Natasha J and Stutterd, Chloe A and McGillivray, George and Yap, Patrick and Regan, Matthew and Chong, Belinda and Fanjul Fernandez, Miriam and Marum, Justine and Phelan, Dean and Pais, Lynn S and White, Susan M and Lunke, Sebastian and Tan, Tiong Y} } @article {913, title = {Missense variant contribution to USP9X-female syndrome.}, journal = {NPJ Genom Med}, volume = {5}, year = {2020}, month = {2020 Dec 09}, pages = {53}, abstract = {

USP9X is an X-chromosome gene that escapes X-inactivation. Loss or compromised function of USP9X leads to neurodevelopmental disorders in males and females. While males are impacted primarily by hemizygous partial loss-of-function missense variants, in females de novo heterozygous complete loss-of-function mutations predominate, and give rise to the clinically recognisable USP9X-female syndrome. Here we provide evidence of the contribution of USP9X missense and small in-frame deletion variants in USP9X-female syndrome also. We scrutinise the pathogenicity of eleven such variants, ten of which were novel. Combined application of variant prediction algorithms, protein structure modelling, and assessment under clinically relevant guidelines universally support their pathogenicity. The core phenotype of this cohort overlapped with previous descriptions of USP9X-female syndrome, but exposed heightened variability. Aggregate phenotypic information of 35 currently known females with predicted pathogenic variation in USP9X reaffirms the clinically recognisable USP9X-female syndrome, and highlights major differences when compared to USP9X-male associated neurodevelopmental disorders.

}, issn = {2056-7944}, doi = {10.1038/s41525-020-00162-9}, author = {Jolly, Lachlan A and Parnell, Euan and Gardner, Alison E and Corbett, Mark A and P{\'e}rez-Jurado, Luis A and Shaw, Marie and Lesca, Gaetan and Keegan, Catherine and Schneider, Michael C and Griffin, Emily and Maier, Felicitas and Kiss, Courtney and Guerin, Andrea and Crosby, Kathleen and Rosenbaum, Kenneth and Tanpaiboon, Pranoot and Whalen, Sandra and Keren, Boris and McCarrier, Julie and Basel, Donald and Sadedin, Simon and White, Susan M and Delatycki, Martin B and Kleefstra, Tjitske and K{\"u}ry, S{\'e}bastien and Brusco, Alfredo and Sukarova-Angelovska, Elena and Trajkova, Slavica and Yoon, Sehoun and Wood, Stephen A and Piper, Michael and Penzes, Peter and Gecz, Jozef} } @article {725, title = {Bioinformatics-Based Identification of Expanded Repeats: A Non-reference Intronic Pentamer Expansion in RFC1 Causes CANVAS.}, journal = {Am J Hum Genet}, volume = {105}, year = {2019}, month = {2019 Jul 03}, pages = {151-165}, abstract = {

Genomic technologies such as next-generation sequencing (NGS) are revolutionizing molecular diagnostics and clinical medicine. However, these approaches have proven inefficient at identifying pathogenic repeat expansions. Here, we apply a collection of bioinformatics tools that can be utilized to identify either known or novel expanded repeat sequences in NGS data. We performed genetic studies of a cohort of 35 individuals from 22 families with a clinical diagnosis of cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Analysis of whole-genome sequence (WGS) data with five independent algorithms identified a recessively inherited intronic repeat expansion [(AAGGG)] in the gene encoding Replication Factor C1 (RFC1). This motif, not reported in the reference sequence, localized to an Alu element and replaced the reference (AAAAG) short tandem repeat. Genetic analyses confirmed the pathogenic expansion in 18 of 22 CANVAS-affected families and identified a core ancestral haplotype, estimated to have arisen in Europe more than twenty-five thousand years ago. WGS of the four RFC1-negative CANVAS-affected families identified plausible variants in three, with genomic re-diagnosis of SCA3, spastic ataxia of the Charlevoix-Saguenay type, and SCA45. This study identified the genetic basis of CANVAS and demonstrated that these improved bioinformatics tools increase the diagnostic utility of WGS to determine the genetic basis of a heterogeneous group of clinically overlapping neurogenetic disorders.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.05.016}, author = {Rafehi, Haloom and Szmulewicz, David J and Bennett, Mark F and Sobreira, Nara L M and Pope, Kate and Smith, Katherine R and Gillies, Greta and Diakumis, Peter and Dolzhenko, Egor and Eberle, Michael A and Barcina, Mar{\'\i}a Garc{\'\i}a and Breen, David P and Chancellor, Andrew M and Cremer, Phillip D and Delatycki, Martin B and Fogel, Brent L and Hackett, Anna and Halmagyi, G Michael and Kapetanovic, Solange and Lang, Anthony and Mossman, Stuart and Mu, Weiyi and Patrikios, Peter and Perlman, Susan L and Rosemergy, Ian and Storey, Elsdon and Watson, Shaun R D and Wilson, Michael A and Zee, David S and Valle, David and Amor, David J and Bahlo, Melanie and Lockhart, Paul J} } @article {728, title = {Pathogenic Variants in GPC4 Cause Keipert Syndrome.}, journal = {Am J Hum Genet}, volume = {104}, year = {2019}, month = {2019 May 02}, pages = {914-924}, abstract = {

Glypicans are a family of cell-surface heparan sulfate proteoglycans that regulate growth-factor signaling during development and are thought to play a role in the regulation of morphogenesis. Whole-exome sequencing of the Australian family that defined Keipert syndrome (nasodigitoacoustic syndrome) identified a hemizygous truncating variant in the gene encoding glypican 4 (GPC4). This variant, located in the final exon of GPC4, results in premature termination of the protein 51 amino acid residues prior to the stop codon, and in concomitant loss of functionally important N-linked glycosylation (Asn514) and glycosylphosphatidylinositol (GPI) anchor (Ser529) sites. We subsequently identified seven affected males from five additional kindreds with novel and predicted pathogenic variants in GPC4. Segregation analysis and X-inactivation studies in carrier females provided supportive evidence that the GPC4 variants caused the condition. Furthermore, functional studies of recombinant protein suggested that the truncated proteins p.Gln506 and p.Glu496 were less stable than the wild type. Clinical features of Keipert syndrome included a prominent forehead, a flat midface, hypertelorism, a broad nose, downturned corners of mouth, and digital abnormalities, whereas cognitive impairment and deafness were variable features. Studies of Gpc4 knockout mice showed evidence of the two primary features of Keipert syndrome: craniofacial abnormalities and digital abnormalities. Phylogenetic analysis demonstrated that GPC4 is most closely related to GPC6, which is associated with a bone dysplasia that has a phenotypic overlap with Keipert syndrome. Overall, we have shown that pathogenic variants in GPC4 cause a loss of function that results in Keipert syndrome, making GPC4 the third human glypican to be linked to a genetic syndrome.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.02.026}, author = {Amor, David J and Stephenson, Sarah E M and Mustapha, Mirna and Mensah, Martin A and Ockeloen, Charlotte W and Lee, Wei Shern and Tankard, Rick M and Phelan, Dean G and Shinawi, Marwan and de Brouwer, Arjan P M and Pfundt, Rolph and Dowling, Cari and Toler, Tomi L and Sutton, V Reid and Agolini, Emanuele and Rinelli, Martina and Capolino, Rossella and Martinelli, Diego and Zampino, Giuseppe and Dumi{\'c}, Miroslav and Reardon, William and Shaw-Smith, Charles and Leventer, Richard J and Delatycki, Martin B and Kleefstra, Tjitske and Mundlos, Stefan and Mortier, Geert and Bahlo, Melanie and Allen, Nicola J and Lockhart, Paul J} } @article {258, title = {Expanding the phenotypic spectrum of ARID1B-mediated disorders and identification of altered cell-cycle dynamics due to ARID1B haploinsufficiency.}, journal = {Orphanet J Rare Dis}, volume = {9}, year = {2014}, month = {2014 Mar 27}, pages = {43}, abstract = {

BACKGROUND: Mutations in genes encoding components of the Brahma-associated factor (BAF) chromatin remodeling complex have recently been shown to contribute to multiple syndromes characterised by developmental delay and intellectual disability. ARID1B mutations have been identified as the predominant cause of Coffin-Siris syndrome and have also been shown to be a frequent cause of nonsyndromic intellectual disability. Here, we investigate the molecular basis of a patient with an overlapping but distinctive phenotype of intellectual disability, plantar fat pads and facial dysmorphism.

METHODS/RESULTS: High density microarray analysis of the patient demonstrated a heterozygous deletion at 6q25.3, which resulted in the loss of four genes including AT Rich Interactive Domain 1B (ARID1B). Subsequent quantitative real-time PCR analysis revealed ARID1B haploinsufficiency in the patient. Analysis of both patient-derived and ARID1B knockdown fibroblasts after serum starvation demonstrated delayed cell cycle re-entry associated with reduced cell number in the S1 phase. Based on the patient{\textquoteright}s distinctive phenotype, we ascertained four additional patients and identified heterozygous de novo ARID1B frameshift or nonsense mutations in all of them.

CONCLUSIONS: This study broadens the spectrum of ARID1B associated phenotypes by describing a distinctive phenotype including plantar fat pads but lacking the hypertrichosis or fifth nail hypoplasia associated with Coffin-Siris syndrome. We present the first direct evidence in patient-derived cells that alterations in cell cycle contribute to the underlying pathogenesis of syndromes associated with ARID1B haploinsufficiency.

}, keywords = {Abnormalities, Multiple, Cell Cycle, Chromatin Assembly and Disassembly, DNA-Binding Proteins, Face, Female, Hand Deformities, Congenital, Haploinsufficiency, Humans, Intellectual Disability, Male, Micrognathism, Neck, Transcription Factors}, issn = {1750-1172}, doi = {10.1186/1750-1172-9-43}, author = {Sim, Joe C H and White, Susan M and Fitzpatrick, Elizabeth and Wilson, Gabrielle R and Gillies, Greta and Pope, Kate and Mountford, Hayley S and Torring, Pernille M and McKee, Shane and Vulto-van Silfhout, Anneke T and Jhangiani, Shalini N and Muzny, Donna M and Leventer, Richard J and Delatycki, Martin B and Amor, David J and Lockhart, Paul J} }