Laura M L Carvalho1, Carla S D'Angelo2, Zan Mustacchi3, Israel T da Silva4, Ana Cristina V Krepischi5, Celia P Koiffmann6, Carla Rosenberg7. 1. Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of Sao Paulo (USP), Sao Paulo, SP, Brazil. Electronic address: lauralara@usp.br. 2. Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of Sao Paulo (USP), Sao Paulo, SP, Brazil. Electronic address: carlasustek@gmail.com. 3. Genetic Outpatient Clinic of the Darcy Vargas Children's Hospital (HIDV), São Paulo, SP, Brazil; São Paulo Center for Clinical Studies and Research - CEPEC-SP, São Paulo, SP, Brazil. Electronic address: drzan@drzan.com.br. 4. International Center for Research, A. C. Camargo Cancer Center, Sao Paulo, Brazil. Electronic address: itojal@accamargo.org.br. 5. Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of Sao Paulo (USP), Sao Paulo, SP, Brazil. Electronic address: ana.krepischi@ib.usp.br. 6. Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of Sao Paulo (USP), Sao Paulo, SP, Brazil. Electronic address: cpkoiffm@ib.usp.br. 7. Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of Sao Paulo (USP), Sao Paulo, SP, Brazil. Electronic address: carlarosenberg@ib.usp.br.
Abstract
BACKGROUND: Pathogenic variants involving the MYT1L gene lead to an autosomal dominant form of syndromic obesity, characterized by polyphagia, intellectual disability/developmental delay, and behavioral problems, and that a characteristic facial phenotype does not seem to be recognizable. METHODS: Trio whole exome sequencing was performed in a 10-year-old Brazilian male presenting polyphagia, severe early-onset obesity, intellectual disability, speech delay, macrocephaly, frontal bossing, telecanthus, strabismus, and hypogenitalism. Additionally, we performed a literature review of patients carrying non-copy number MYT1L variants. RESULTS: A de novo genetic variant not previously reported in MYT1L (NM_015025.4:c.2990C>A) was identified in the proband and classified as pathogenic. From a literature search, 22 further patients carrying non-copy number MYT1L variants were identified, evidencing that although the associated phenotype is quite variable, intellectual disability/developmental and speech delays are always present. Further, most patients have obesity or overweight due to polyphagia. Macrocephaly, strabismus, behavioral problems, and hand/feet malformations are also recurrent features. CONCLUSIONS: We described the first Brazilian case of MYT1L related syndrome and highlighted clinical characteristics based on the literature. Other syndromic forms of obesity such as Prader-Willi, Bardet-Biedl, Börjeson-Forssman-Lehmann, MORM, Cohen, Alstrom, and Kleefstra type 1 syndromes should be considered in the differential diagnosis. Further, although obesity is frequent, it is not an obligatory feature of all carriers of MYT1L mutations.
BACKGROUND: Pathogenic variants involving the MYT1L gene lead to an autosomal dominant form of syndromic obesity, characterized by polyphagia, intellectual disability/developmental delay, and behavioral problems, and that a characteristic facial phenotype does not seem to be recognizable. METHODS:Trio whole exome sequencing was performed in a 10-year-old Brazilian male presenting polyphagia, severe early-onset obesity, intellectual disability, speech delay, macrocephaly, frontal bossing, telecanthus, strabismus, and hypogenitalism. Additionally, we performed a literature review of patients carrying non-copy number MYT1L variants. RESULTS: A de novo genetic variant not previously reported in MYT1L (NM_015025.4:c.2990C>A) was identified in the proband and classified as pathogenic. From a literature search, 22 further patients carrying non-copy number MYT1L variants were identified, evidencing that although the associated phenotype is quite variable, intellectual disability/developmental and speech delays are always present. Further, most patients have obesity or overweight due to polyphagia. Macrocephaly, strabismus, behavioral problems, and hand/feet malformations are also recurrent features. CONCLUSIONS: We described the first Brazilian case of MYT1L related syndrome and highlighted clinical characteristics based on the literature. Other syndromic forms of obesity such as Prader-Willi, Bardet-Biedl, Börjeson-Forssman-Lehmann, MORM, Cohen, Alstrom, and Kleefstra type 1 syndromes should be considered in the differential diagnosis. Further, although obesity is frequent, it is not an obligatory feature of all carriers of MYT1L mutations.
Authors: Markus Wöhr; Wendy M Fong; Justyna A Janas; Moritz Mall; Christian Thome; Madhuri Vangipuram; Lingjun Meng; Thomas C Südhof; Marius Wernig Journal: Mol Autism Date: 2022-05-10 Impact factor: 6.476