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Association of Disparities in Family History and Family Cancer History in the Electronic Health Record With Sex, Race, Hispanic or Latino Ethnicity, and Language Preference in 2 Large US Health Care Systems

Chavez-Yenter, Daniel; Goodman, Melody S; Chen, Yuyu; Chu, Xiangying; Bradshaw, Richard L; Lorenz Chambers, Rachelle; Chan, Priscilla A; Daly, Brianne M; Flynn, Michael; Gammon, Amanda; Hess, Rachel; Kessler, Cecelia; Kohlmann, Wendy K; Mann, Devin M; Monahan, Rachel; Peel, Sara; Kawamoto, Kensaku; Del Fiol, Guilherme; Sigireddi, Meenakshi; Buys, Saundra S; Ginsburg, Ophira; Kaphingst, Kimberly A
Importance:Clinical decision support (CDS) algorithms are increasingly being implemented in health care systems to identify patients for specialty care. However, systematic differences in missingness of electronic health record (EHR) data may lead to disparities in identification by CDS algorithms. Objective:To examine the availability and comprehensiveness of cancer family history information (FHI) in patients' EHRs by sex, race, Hispanic or Latino ethnicity, and language preference in 2 large health care systems in 2021. Design, Setting, and Participants:This retrospective EHR quality improvement study used EHR data from 2 health care systems: University of Utah Health (UHealth) and NYU Langone Health (NYULH). Participants included patients aged 25 to 60 years who had a primary care appointment in the previous 3 years. Data were collected or abstracted from the EHR from December 10, 2020, to October 31, 2021, and analyzed from June 15 to October 31, 2021. Exposures:Prior collection of cancer FHI in primary care settings. Main Outcomes and Measures:Availability was defined as having any FHI and any cancer FHI in the EHR and was examined at the patient level. Comprehensiveness was defined as whether a cancer family history observation in the EHR specified the type of cancer diagnosed in a family member, the relationship of the family member to the patient, and the age at onset for the family member and was examined at the observation level. Results:Among 144 484 patients in the UHealth system, 53.6% were women; 74.4% were non-Hispanic or non-Latino and 67.6% were White; and 83.0% had an English language preference. Among 377 621 patients in the NYULH system, 55.3% were women; 63.2% were non-Hispanic or non-Latino, and 55.3% were White; and 89.9% had an English language preference. Patients from historically medically undeserved groups-specifically, Black vs White patients (UHealth: 17.3% [95% CI, 16.1%-18.6%] vs 42.8% [95% CI, 42.5%-43.1%]; NYULH: 24.4% [95% CI, 24.0%-24.8%] vs 33.8% [95% CI, 33.6%-34.0%]), Hispanic or Latino vs non-Hispanic or non-Latino patients (UHealth: 27.2% [95% CI, 26.5%-27.8%] vs 40.2% [95% CI, 39.9%-40.5%]; NYULH: 24.4% [95% CI, 24.1%-24.7%] vs 31.6% [95% CI, 31.4%-31.8%]), Spanish-speaking vs English-speaking patients (UHealth: 18.4% [95% CI, 17.2%-19.1%] vs 40.0% [95% CI, 39.7%-40.3%]; NYULH: 15.1% [95% CI, 14.6%-15.6%] vs 31.1% [95% CI, 30.9%-31.2%), and men vs women (UHealth: 30.8% [95% CI, 30.4%-31.2%] vs 43.0% [95% CI, 42.6%-43.3%]; NYULH: 23.1% [95% CI, 22.9%-23.3%] vs 34.9% [95% CI, 34.7%-35.1%])-had significantly lower availability and comprehensiveness of cancer FHI (P < .001). Conclusions and Relevance:These findings suggest that systematic differences in the availability and comprehensiveness of FHI in the EHR may introduce informative presence bias as inputs to CDS algorithms. The observed differences may also exacerbate disparities for medically underserved groups. System-, clinician-, and patient-level efforts are needed to improve the collection of FHI.
PMID: 36194411
ISSN: 2574-3805
CID: 5351532

De Novo ZMYND8 variants result in an autosomal dominant neurodevelopmental disorder with cardiac malformations

Dias, Kerith-Rae; Carlston, Colleen M; Blok, Laura E R; De Hayr, Lachlan; Nawaz, Urwah; Evans, Carey-Anne; Bayrak-Toydemir, Pinar; Htun, Stephanie; Zhu, Ying; Ma, Alan; Lynch, Sally Ann; Moorwood, Catherine; Stals, Karen; Ellard, Sian; Bainbridge, Matthew N; Friedman, Jennifer; Pappas, John G; Rabin, Rachel; Nowak, Catherine B; Douglas, Jessica; Wilson, Theodore E; Guillen Sacoto, Maria J; Mullegama, Sureni V; Palculict, Timothy Blake; Kirk, Edwin P; Pinner, Jason R; Edwards, Matthew; Montanari, Francesca; Graziano, Claudio; Pippucci, Tommaso; Dingmann, Bri; Glass, Ian; Mefford, Heather C; Shimoji, Takeyoshi; Suzuki, Toshimitsu; Yamakawa, Kazuhiro; Streff, Haley; Schaaf, Christian P; Slavotinek, Anne M; Voineagu, Irina; Carey, John C; Buckley, Michael F; Schenck, Annette; Harvey, Robert J; Roscioli, Tony
PURPOSE/OBJECTIVE:ZMYND8 encodes a multidomain protein that serves as a central interactive hub for coordinating critical roles in transcription regulation, chromatin remodeling, regulation of super-enhancers, DNA damage response and tumor suppression. We delineate a novel neurocognitive disorder caused by variants in the ZMYND8 gene. METHODS:An international collaboration, exome sequencing, molecular modeling, yeast two-hybrid assays, analysis of available transcriptomic data and a knockdown Drosophila model were used to characterize the ZMYND8 variants. RESULTS:ZMYND8 variants were identified in 11 unrelated individuals; 10 occurred de novo and one suspected de novo; 2 were truncating, 9 were missense, of which one was recurrent. The disorder is characterized by intellectual disability with variable cardiovascular, ophthalmologic and minor skeletal anomalies. Missense variants in the PWWP domain of ZMYND8 abolish the interaction with Drebrin and missense variants in the MYND domain disrupt the interaction with GATAD2A. ZMYND8 is broadly expressed across cell types in all brain regions and shows highest expression in the early stages of brain development. Neuronal knockdown of the DrosophilaZMYND8 ortholog results in decreased habituation learning, consistent with a role in cognitive function. CONCLUSION/CONCLUSIONS:We present genomic and functional evidence for disruption of ZMYND8 as a novel etiology of syndromic intellectual disability.
PMID: 35916866
ISSN: 1530-0366
CID: 5287932

Heterozygous variants in CTR9, which encodes a major component of the PAF1 complex, are associated with a neurodevelopmental disorder

Meuwissen, Marije; Verstraeten, Aline; Ranza, Emmanuelle; Iwaszkiewicz, Justyna; Bastiaansen, Maaike; Mateiu, Ligia; Nemegeer, Merlijn; Meester, Josephina A N; Afenjar, Alexandra; Amaral, Michelle; Ballhausen, Diana; Barnett, Sarah; Barth, Magalie; Asselbergh, Bob; Spaas, Katrien; Heeman, Bavo; Bassetti, Jennifer; Blackburn, Patrick; Schaer, Marie; Blanc, Xavier; Zoete, Vincent; Casas, Kari; Courtin, Thomas; Doummar, Diane; Guerry, Frédéric; Keren, Boris; Pappas, John; Rabin, Rachel; Begtrup, Amber; Shinawi, Marwan; Vulto-van Silfhout, Anneke T; Kleefstra, Tjitske; Wagner, Matias; Ziegler, Alban; Schaefer, Elise; Gerard, Benedicte; De Bie, Charlotte I; Holwerda, Sjoerd J B; Abbot, Mary Alice; Antonarakis, Stylianos E; Loeys, Bart
PURPOSE/OBJECTIVE:CTR9 is a subunit of the PAF1 complex (PAF1C) that plays a crucial role in transcription regulation by binding CTR9 to RNA polymerase II. It is involved in transcription-coupled histone modification through promoting H3K4 and H3K36 methylation. We describe the clinical and molecular studies in 13 probands, harboring likely pathogenic CTR9 missense variants, collected through GeneMatcher. METHODS:Exome sequencing was performed in all individuals. CTR9 variants were assessed through 3-dimensional modeling of the activated human transcription complex Pol II-DSIF-PAF-SPT6 and the PAF1/CTR9 complex. H3K4/H3K36 methylation analysis, mitophagy assessment based on tetramethylrhodamine ethyl ester perchlorate immunofluorescence, and RNA-sequencing in skin fibroblasts from 4 patients was performed. RESULTS:Common clinical findings were variable degrees of intellectual disability, hypotonia, joint hyperlaxity, speech delay, coordination problems, tremor, and autism spectrum disorder. Mild dysmorphism and cardiac anomalies were less frequent. For 11 CTR9 variants, de novo occurrence was shown. Three-dimensional modeling predicted a likely disruptive effect of the variants on local CTR9 structure and protein interaction. Additional studies in fibroblasts did not unveil the downstream functional consequences of the identified variants. CONCLUSION/CONCLUSIONS:We describe a neurodevelopmental disorder caused by (mainly) de novo variants in CTR9, likely affecting PAF1C function.
PMID: 35499524
ISSN: 1530-0366
CID: 5215882

De novo mutations in childhood cases of sudden unexplained death that disrupt intracellular Ca2+ regulation

Halvorsen, Matthew; Gould, Laura; Wang, Xiaohan; Grant, Gariel; Moya, Raquel; Rabin, Rachel; Ackerman, Michael J; Tester, David J; Lin, Peter T; Pappas, John G; Maurano, Matthew T; Goldstein, David B; Tsien, Richard W; Devinsky, Orrin
Sudden unexplained death in childhood (SUDC) is an understudied problem. Whole-exome sequence data from 124 "trios" (decedent child, living parents) was used to test for excessive de novo mutations (DNMs) in genes involved in cardiac arrhythmias, epilepsy, and other disorders. Among decedents, nonsynonymous DNMs were enriched in genes associated with cardiac and seizure disorders relative to controls (odds ratio = 9.76, P = 2.15 × 10-4). We also found evidence for overtransmission of loss-of-function (LoF) or previously reported pathogenic variants in these same genes from heterozygous carrier parents (11 of 14 transmitted, P = 0.03). We identified a total of 11 SUDC proband genotypes (7 de novo, 1 transmitted parental mosaic, 2 transmitted parental heterozygous, and 1 compound heterozygous) as pathogenic and likely contributory to death, a genetic finding in 8.9% of our cohort. Two genes had recurrent missense DNMs, RYR2 and CACNA1C Both RYR2 mutations are pathogenic (P = 1.7 × 10-7) and were previously studied in mouse models. Both CACNA1C mutations lie within a 104-nt exon (P = 1.0 × 10-7) and result in slowed L-type calcium channel inactivation and lower current density. In total, six pathogenic DNMs can alter calcium-related regulation of cardiomyocyte and neuronal excitability at a submembrane junction, suggesting a pathway conferring susceptibility to sudden death. There was a trend for excess LoF mutations in LoF intolerant genes, where ≥1 nonhealthy sample in denovo-db has a similar variant (odds ratio = 6.73, P = 0.02); additional uncharacterized genetic causes of sudden death in children might be discovered with larger cohorts.
PMID: 34930847
ISSN: 1091-6490
CID: 5108732

Expanding the phenotype of ASXL3-related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3

Schirwani, Schaida; Albaba, Shadi; Carere, Deanna Alexis; Guillen Sacoto, Maria J; Milan Zamora, Francisca; Si, Yue; Rabin, Rachel; Pappas, John; Renaud, Deborah L; Hauser, Natalie; Reid, Evan; Blanchet, Patricia; Foulds, Nichola; Dixit, Abhijit; Fisher, Richard; Armstrong, Ruth; Isidor, Bertrand; Cogne, Benjamin; Schrier Vergano, Samantha; Demirdas, Serwet; Dykzeul, Natalie; Cohen, Julie S; Grand, Katheryn; Morel, Dayna; Slavotinek, Anne; Albassam, Hessa F; Naik, Swati; Dean, John; Ragge, Nicola; Cinzia, Costa; Tedesco, Maria Giovanna; Harrison, Rachel E; Bouman, Arjan; Palen, Emily; Challman, Thomas D; Willemsen, Marjolein H; Vogt, Julie; Cunniff, Christopher; Bergstrom, Katherine; Walia, Jagdeep S; Bruel, Ange-Line; Kini, Usha; Alkuraya, Fowzan S; Slegesky, Valerie; Meeks, Naomi; Girotto, Paula; Johnson, Diana; Newbury-Ecob, Ruth; Ockeloen, Charlotte W; Prontera, Paolo; Lynch, Sally Ann; Li, Dong; Graham, John M; Balasubramanian, Meena
The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low-hanging columella. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants.
PMID: 34436830
ISSN: 1552-4833
CID: 5011592

PPP3CA truncating variants clustered in the regulatory domain cause early-onset refractory epilepsy

Panneerselvam, Sugi; Wang, Julia; Zhu, Wenmiao; Dai, Hongzheng; Pappas, John G; Rabin, Rachel; Low, Karen J; Rosenfeld, Jill A; Emrick, Lisa; Xiao, Rui; Xia, Fan; Yang, Yaping; Eng, Christine M; Anderson, Anne; Chau, Vann; Soler-Alfonso, Claudia; Streff, Haley; Lalani, Seema R; Mercimek-Andrews, Saadet; Bi, Weimin
PPP3CA encodes the catalytic subunit of calcineurin, a calcium-calmodulin-regulated serine-threonine phosphatase. Loss-of-function (LoF) variants in the catalytic domain have been associated with epilepsy, while gain-of-function (GoF) variants in the auto-inhibitory domain cause multiple congenital abnormalities. We herein report five new patients with de novo PPP3CA variants. Interestingly, the two frameshift variants in this study and the six truncating variants reported previously are all located within a 26-amino acid region in the regulatory domain (RD). Patients with a truncating variant had more severe earlier onset seizures compared to patients with a LoF missense variant, while autism spectrum disorder was a more frequent feature in the latter. Expression studies of a truncating variant showed apparent RNA expression from the mutant allele, but no detectable mutant protein. Our data suggest that PPP3CA truncating variants clustered in the RD, causing more severe early-onset refractory epilepsy and representing a type of variants distinct from LoF or GoF missense variants.
PMID: 33963760
ISSN: 1399-0004
CID: 4878142

A synonymous variant in MYO15A enriched in the Ashkenazi Jewish population causes autosomal recessive hearing loss due to abnormal splicing

Hirsch, Yoel; Tangshewinsirikul, Chayada; Booth, Kevin T; Azaiez, Hela; Yefet, Devorah; Quint, Adina; Weiden, Tzvi; Brownstein, Zippora; Macarov, Michal; Davidov, Bella; Pappas, John; Rabin, Rachel; Kenna, Margaret A; Oza, Andrea M; Lafferty, Katherine; Amr, Sami S; Rehm, Heidi L; Kolbe, Diana L; Frees, Kathy; Nishimura, Carla; Luo, Minjie; Farra, Chantal; Morton, Cynthia C; Scher, Sholem Y; Ekstein, Josef; Avraham, Karen B; Smith, Richard J H; Shen, Jun
Nonsyndromic hearing loss is genetically heterogeneous. Despite comprehensive genetic testing, many cases remain unsolved because the clinical significance of identified variants is uncertain or because biallelic pathogenic variants are not identified for presumed autosomal recessive cases. Common synonymous variants are often disregarded. Determining the pathogenicity of synonymous variants may improve genetic diagnosis. We report a synonymous variant c.9861 C > T/p.(Gly3287=) in MYO15A in homozygosity or compound heterozygosity with another pathogenic or likely pathogenic MYO15A variant in 10 unrelated families with nonsyndromic sensorineural hearing loss. Biallelic variants in MYO15A were identified in 21 affected and were absent in 22 unaffected siblings. A mini-gene assay confirms that the synonymous variant leads to abnormal splicing. The variant is enriched in the Ashkenazi Jewish population. Individuals carrying biallelic variants involving c.9861 C > T often exhibit progressive post-lingual hearing loss distinct from the congenital profound deafness typically associated with biallelic loss-of-function MYO15A variants. This study establishes the pathogenicity of the c.9861 C > T variant in MYO15A and expands the phenotypic spectrum of MYO15A-related hearing loss. Our work also highlights the importance of multicenter collaboration and data sharing to establish the pathogenicity of a relatively common synonymous variant for improved diagnosis and management of hearing loss.
PMID: 33398081
ISSN: 1476-5438
CID: 4747522

CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants

Zarate, Yuri A; Uehara, Tomoko; Abe, Kota; Oginuma, Masayuki; Harako, Sora; Ishitani, Shizuka; Lehesjoki, Anna-Elina; Bierhals, Tatjana; Kloth, Katja; Ehmke, Nadja; Horn, Denise; Holtgrewe, Manuel; Anderson, Katherine; Viskochil, David; Edgar-Zarate, Courtney L; Sacoto, Maria J Guillen; Schnur, Rhonda E; Morrow, Michelle M; Sanchez-Valle, Amarilis; Pappas, John; Rabin, Rachel; Muona, Mikko; Anttonen, Anna-Kaisa; Platzer, Konrad; Luppe, Johannes; Gburek-Augustat, Janina; Kaname, Tadashi; Okamoto, Nobuhiko; Mizuno, Seiji; Kaido, Yusaku; Ohkuma, Yoshiaki; Hirose, Yutaka; Ishitani, Tohru; Kosaki, Kenjiro
PURPOSE/OBJECTIVE:To expand the recent description of a new neurodevelopmental syndrome related to alterations in CDK19. METHODS:. RESULTS:We describe 11 unrelated individuals (age range: 9 months to 14 years) with de novo missense variants mapped to the kinase domain of CDK19, including two recurrent changes at residues Tyr32 and Gly28. In vitro autophosphorylation and substrate phosphorylation assays revealed that kinase activity of protein was lower for p.Gly28Arg and higher for p.Tyr32His substitutions compared with that of the wild-type protein. Injection of CDK19 messenger RNA (mRNA) with either the Tyr32His or the Gly28Arg variants using in vivo zebrafish model significantly increased fraction of embryos with morphological abnormalities. Overall, the phenotype of the now 14 individuals with CDK19-related disorder includes universal developmental delay and facial dysmorphism, hypotonia (79%), seizures (64%), ophthalmologic anomalies (64%), and autism/autistic traits (56%). CONCLUSION/CONCLUSIONS:CDK19 de novo missense variants are responsible for a novel neurodevelopmental disorder. Both kinase assay and zebrafish experiments showed that the pathogenetic mechanism may be more diverse than previously thought.
PMID: 33495529
ISSN: 1530-0366
CID: 4771732

Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders

Gillentine, Madelyn A; Wang, Tianyun; Hoekzema, Kendra; Rosenfeld, Jill; Liu, Pengfei; Guo, Hui; Kim, Chang N; De Vries, Bert B A; Vissers, Lisenka E L M; Nordenskjold, Magnus; Kvarnung, Malin; Lindstrand, Anna; Nordgren, Ann; Gecz, Jozef; Iascone, Maria; Cereda, Anna; Scatigno, Agnese; Maitz, Silvia; Zanni, Ginevra; Bertini, Enrico; Zweier, Christiane; Schuhmann, Sarah; Wiesener, Antje; Pepper, Micah; Panjwani, Heena; Torti, Erin; Abid, Farida; Anselm, Irina; Srivastava, Siddharth; Atwal, Paldeep; Bacino, Carlos A; Bhat, Gifty; Cobian, Katherine; Bird, Lynne M; Friedman, Jennifer; Wright, Meredith S; Callewaert, Bert; Petit, Florence; Mathieu, Sophie; Afenjar, Alexandra; Christensen, Celenie K; White, Kerry M; Elpeleg, Orly; Berger, Itai; Espineli, Edward J; Fagerberg, Christina; Brasch-Andersen, Charlotte; Hansen, Lars Kjærsgaard; Feyma, Timothy; Hughes, Susan; Thiffault, Isabelle; Sullivan, Bonnie; Yan, Shuang; Keller, Kory; Keren, Boris; Mignot, Cyril; Kooy, Frank; Meuwissen, Marije; Basinger, Alice; Kukolich, Mary; Philips, Meredith; Ortega, Lucia; Drummond-Borg, Margaret; Lauridsen, Mathilde; Sorensen, Kristina; Lehman, Anna; Lopez-Rangel, Elena; Levy, Paul; Lessel, Davor; Lotze, Timothy; Madan-Khetarpal, Suneeta; Sebastian, Jessica; Vento, Jodie; Vats, Divya; Benman, L Manace; Mckee, Shane; Mirzaa, Ghayda M; Muss, Candace; Pappas, John; Peeters, Hilde; Romano, Corrado; Elia, Maurizio; Galesi, Ornella; Simon, Marleen E H; van Gassen, Koen L I; Simpson, Kara; Stratton, Robert; Syed, Sabeen; Thevenon, Julien; Palafoll, Irene Valenzuela; Vitobello, Antonio; Bournez, Marie; Faivre, Laurence; Xia, Kun; Earl, Rachel K; Nowakowski, Tomasz; Bernier, Raphael A; Eichler, Evan E
BACKGROUND:With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations. METHODS:We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk. RESULTS:We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs. CONCLUSIONS:Overall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.
PMID: 33874999
ISSN: 1756-994x
CID: 4897582

EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum

Hüffmeier, Ulrike; Kraus, Cornelia; Reuter, Miriam S; Uebe, Steffen; Abbott, Mary-Alice; Ahmed, Syed A; Rawson, Kristyn L; Barr, Eileen; Li, Hong; Bruel, Ange-Line; Faivre, Laurence; Tran Mau-Them, Frédéric; Botti, Christina; Brooks, Susan; Burns, Kaitlyn; Ward, D Isum; Dutra-Clarke, Marina; Martinez-Agosto, Julian A; Lee, Hane; Nelson, Stanley F; Zacher, Pia; Abou Jamra, Rami; Klöckner, Chiara; McGaughran, Julie; Kohlhase, Jürgen; Schuhmann, Sarah; Moran, Ellen; Pappas, John; Raas-Rothschild, Annick; Sacoto, Maria J Guillen; Henderson, Lindsay B; Palculict, Timothy Blake; Mullegama, Sureni V; Zghal Elloumi, Houda; Reich, Adi; Schrier Vergano, Samantha A; Wahl, Erica; Reis, André; Zweier, Christiane
BACKGROUND:An identical homozygous missense variant in EIF3F, identified through a large-scale genome-wide sequencing approach, was reported as causative in nine individuals with a neurodevelopmental disorder, characterized by variable intellectual disability, epilepsy, behavioral problems and sensorineural hearing-loss. To refine the phenotypic and molecular spectrum of EIF3F-related neurodevelopmental disorder, we examined independent patients. RESULTS:21 patients were homozygous and one compound heterozygous for c.694T>G/p.(Phe232Val) in EIF3F. Haplotype analyses in 15 families suggested that c.694T>G/p.(Phe232Val) was a founder variant. All affected individuals had developmental delays including delayed speech development. About half of the affected individuals had behavioral problems, altered muscular tone, hearing loss, and short stature. Moreover, this study suggests that microcephaly, reduced sensitivity to pain, cleft lip/palate, gastrointestinal symptoms and ophthalmological symptoms are part of the phenotypic spectrum. Minor dysmorphic features were observed, although neither the individuals' facial nor general appearance were obviously distinctive. Symptoms in the compound heterozygous individual with an additional truncating variant were at the severe end of the spectrum in regard to motor milestones, speech delay, organic problems and pre- and postnatal growth of body and head, suggesting some genotype-phenotype correlation. CONCLUSIONS:Our study refines the phenotypic and expands the molecular spectrum of EIF3F-related syndromic neurodevelopmental disorder.
PMID: 33736665
ISSN: 1750-1172
CID: 4836122