Variants in DONSON were recently identified as the cause of microcephaly, short stature, and limb abnormalities syndrome (MISSLA). The clinical spectra of MISSLA and Fanconi anaemia (FA) strongly overlap. For that reason, some MISSLA patients have been clinically diagnosed with FA. Here, we present the clinical data of siblings with MISSLA featuring a novel DONSON variant and summarize the current literature on MISSLA. Additionally, we perform computer-aided image analysis using the DeepGestalt technology to test how distinct the facial features of MISSLA and FA patients are. We show that MISSLA has a specific facial gestalt. Notably, we find that also FA patients feature facial characteristics recognizable by computer-aided image analysis. We conclude that computer-assisted image analysis improves diagnostic precision in both MISSLA and FA.
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Hart TC, Hart PS. Genetic studies of craniofacial anomalies: clinical implications and applications. Orthod Craniofac Res. 2009;12:212–20.
Lumaka A, Cosemans N, Lulebo Mampasi A, Mubungu G, Mvuama N, Lubala T. et al. Facial dysmorphism is influenced by ethnic background of the patient and of the evaluator. Clin Genet. 2017;92:166–71.
Basel-Vanagaite L, Wolf L, Orin M, Larizza L, Gervasini C, Krantz ID. et al. Recognition of the Cornelia de Lange syndrome phenotype with facial dysmorphology novel analysis. Clin Genet. 2016;89:557–63.
Gurovich Y, Hanani Y, Bar O, Fleischer N, Gelbman D, Basel-Salmon L. et al. Identifying facial phenotypes of genetic disorders using deep learning. Nat Med. 2019;25:60–64.
Gripp KW, Baker L, Telegrafi A, Monaghan KG. The role of objective facial analysis using FDNA in making diagnoses following whole exome analysis. Report of two patients with mutations in the BAF complex genes. Am J Med Genet A. 2016;170:1754–62.
Gardner OK, Haynes K, Schweitzer D, Johns A, Magee WP, Urata MM. et al. Familial recurrence of 3MC syndrome in consanguineous families: a clinical and molecular diagnostic approach with review of the literature. Cleft Palate Craniofac J. 2017;54:739–48.
Graul-Neumann LM, Mensah MA, Klopocki E, Uebe S, Ekici AB, Thiel CT. et al. Biallelic intragenic deletion in MASP1 in an adult female with 3MC syndrome. Eur J Med Genet. 2018;61:363–8.
Liehr T, Acquarola N, Pyle K, St-Pierre S, Rinholm M, Bar O. et al. Next generation phenotyping in Emanuel and Pallister-Killian syndrome using computer-aided facial dysmorphology analysis of 2D photos. Clin Genet. 2018;93:378–81.
Hadj-Rabia S, Schneider H, Navarro E, Klein O, Kirby N, Huttner K. et al. Automatic recognition of the XLHED phenotype from facial images. Am J Med Genet A. 2017;173:2408–14.
Valentine M, Bihm DCJ, Wolf L, Hoyme HE, May PA, Buckley D, et al. Computer-aided recognition of facial attributes for fetal alcohol spectrum disorders. Pediatrics. 2017;140. https://doi.org/10.1542/peds.2016-2028
Knaus A, Pantel JT, Pendziwiat M, Hajjir N, Zhao M, Hsieh T-C, et al. Characterization of glycosylphosphatidylinositol biosynthesis defects by clinical features, flow cytometry, and automated image analysis. Genome Med. 2018;10:3.
Zarate YA, Smith-Hicks CL, Greene C, Abbott M-A, Siu VM, Calhoun ARUL. et al. Natural history and genotype-phenotype correlations in 72 individuals with SATB2-associated syndrome. Am J Med Genet A. 2018;176:925–35.
Pantel JT, Zhao M, Mensah MA, Hajjir N, Hsieh T-C, Hanani Y. et al. Advances in computer-assisted syndrome recognition by the example of inborn errors of metabolism. J Inherit Metab Dis. 2018;41:533–9.
Ferreira CR, Altassan R, Marques-Da-Silva D, Francisco R, Jaeken J, Morava E. Recognizable phenotypes in CDG. J Inherit Metab Dis. 2018;41:541–53.
Jiang Y, Wangler MF, McGuire AL, Lupski JR, Posey JE, Khayat MM. et al. The phenotypic spectrum of Xia-Gibbs syndrome. Am J Med Genet A. 2018;176:1315–26.
Vorravanpreecha N, Lertboonnum T, Rodjanadit R, Sriplienchan P, Rojnueangnit K. Studying Down syndrome recognition probabilities in Thai children with de-identified computer-aided facial analysis. Am J Med Genet A. 2018;176:1935–40.
Mishima H, Suzuki H, Doi M, Miyazaki M, Watanabe S, Matsumoto T, et al. Evaluation of Face2Gene using facial images of patients with congenital dysmorphic syndromes recruited in Japan. J Hum Genet. 2019. https://doi.org/10.1038/s10038-019-0619-z
Carli D, Giorgio E, Pantaleoni F, Bruselles A, Barresi S, Riberi E. et al. NBAS pathogenic variants: defining the associated clinical and facial phenotype and genotype-phenotype correlations. Hum Mutat. 2019;40:721–8.
Hsieh T-C, Mensah MA, Pantel JT, Aguilar D, Bar O, Bayat A, et al. PEDIA: prioritization of exome data by image analysis. Genet Med. 2019. https://doi.org/10.1038/s41436-019-0566-2
Ives EJ, Houston CS. Autosomal recessive microcephaly and micromelia in Cree Indians. Am J Med Genet. 1980;7:351–60.
Milner RD, Khallouf KA, Gibson R, Hajianpour A, Mathew CG. A new autosomal recessive anomaly mimicking Fanconi’s anaemia phenotype. Arch Dis Child. 1993;68:101–3.
Reynolds JJ, Bicknell LS, Carroll P, Higgs MR, Shaheen R, Murray JE. et al. Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism. Nat Genet. 2017;49:537–49.
Evrony GD, Cordero DR, Shen J, Partlow JN, Yu TW, Rodin RE. et al. Integrated genome and transcriptome sequencing identifies a noncoding mutation in the genome replication factor DONSON as the cause of microcephaly-micromelia syndrome. Genome Res. 2017;27:1323–35.
Schulz S, Mensah MA, de Vries H, Fröber R, Romeike B, Schneider U. et al. Microcephaly, short stature, and limb abnormality disorder due to novel autosomal biallelic DONSON mutations in two German siblings. Eur J Hum Genet. 2018;26:1282–7.
Lesly S, Bandura JL, Calvi BR, Rapid DNA. Synthesis during early embryogenesis is sensitive to maternal Humpty Dumpty protein function. Genetics. 2017;207:935–47.
Nordquist S, Smith SR, Pierce J. Systematic functional characterization of human 21st chromosome orthologs in Caenorhabditis elegans. 2017. https://doi.org/10.1101/136911
Mamrak NE, Shimamura A, Howlett NG. Recent discoveries in the molecular pathogenesis of the inherited bone marrow failure syndrome Fanconi anemia. Blood Rev. 2017;31:93–99.
D’Andrea AD. The Fanconi road to cancer. Genes Dev. 2003;17:1933–6.
Yazinski SA, Zou L. Functions, regulation, and therapeutic implications of the ATR checkpoint pathway. Annu Rev Genet. 2016;50:155–73.
Mehta PA, Tolar J. Fanconi anemia. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, et al., editors. GeneReviews. Seattle, WA: University of Washington, Seattle; 2002.
Alter BP. Fanconi anemia and the development of leukemia. Best Pract Res Clin Haematol. 2014;27:214–21.
Alter BP. Inherited bone marrow failure syndromes: considerations pre- and posttransplant. Hematol Am Soc Hematol Educ Program. 2017;2017:88–95.
Joenje H, Patel KJ. The emerging genetic and molecular basis of Fanconi anaemia. Nat Rev Genet. 2001;2:446–57.
Wiedemann H-R. Wiedemanns Atlas klinischer syndrome: Phänomenologie, Ätiologie, Differenzialdiagnose; mit 10 Tabellen. Schattauer Verlag; 2010:125.
Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 2016;536:285–91.
Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM.1000 Genomes Project Consortium et al. A global reference for human genetic variation. Nature. 2015;526:68–74.
Pollard KS, Hubisz MJ, Rosenbloom KR, Siepel A. Detection of nonneutral substitution rates on mammalian phylogenies. Genome Res. 2010;20:110–21.
Schwarz JM, Rödelsperger C, Schuelke M, Seelow D. MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods. 2010;7:575–6.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.
Avila LF, de C, Denis Martins W, Cândido L, Ignácio SA, Bonfim CMS. et al. A study of facial pattern in patients with fanconi anemia. Cleft Palate Craniofac J. 2014;51:83–89.
We thank the families for their cooperation and Carola Dietrich, Nicole Fleischer and Peter Krawitz for technical support. MAM is participant in the BIH Charité Junior Clinician Scientist Program funded by the Charité—Universitätsmedizin Berlin and the Berlin Institute of Health.
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Danyel, M., Cheng, Z., Jung, C. et al. Differentiation of MISSLA and Fanconi anaemia by computer-aided image analysis and presentation of two novel MISSLA siblings. Eur J Hum Genet 27, 1827–1835 (2019). https://doi.org/10.1038/s41431-019-0469-3