Loss-of-Function Variants in MYLK Cause Recessive Megacystis Microcolon Intestinal Hypoperistalsis Syndrome Danny Halim, Erwin Brosens, Françoise Muller,

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Loss-of-Function Variants in MYLK Cause Recessive Megacystis Microcolon Intestinal Hypoperistalsis Syndrome Danny Halim, Erwin Brosens, Françoise Muller, Michael F. Wangler, Arthur L. Beaudet, James R. Lupski, Zeynep H. Coban Akdemir, Michael Doukas, Hans J. Stoop, Bianca M. de Graaf, Rutger W.W. Brouwer, Wilfred F.J. van Ijcken, Jean-François Oury, Jonathan Rosenblatt, Alan J. Burns, Dick Tibboel, Robert M.W. Hofstra, Maria M. Alves The American Journal of Human Genetics Volume 101, Issue 1, Pages 123-129 (July 2017) DOI: 10.1016/j.ajhg.2017.05.011 Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 1 Genetic Analysis and Description of the Three MMIHS Subjects Included in This Study (A) Pedigrees of the two consanguineous families analyzed by Sanger sequencing show the presence of homozygous variants in MYLK. Subject 1 (II-2) and subject 2 (II-3) carry a 7 bp duplication in exon 23 (c.3838_3844dupGAAAGCG [p.Glu1282_Glyfs∗51]), whereas their unaffected sister (II-4) shows no mutant allele. Subject 3 (II-5) has a putative splice-site variant affecting exon 23 (c.3985+5C>A). Both variants are present in a heterozygous state in the parents. (B) Prenatal ultrasonography of subject 1 (II-2) at 13 weeks of gestation revealed a distended bladder and generalized subcutaneous edema. (C) Prenatal ultrasonography of subject 2 (II-3) at 24 weeks revealed a distended bladder, hydronephrosis, and severe oligohydramnios. (D) Barium enema performed in subject 2 (II-3) suggested intestinal obstruction and malrotation. (E) Neonatal ultrasonography of subject 3 (II-5) revealed bladder distension and bilateral hydronephrosis. Abbreviations are as follows: UB, urinary bladder; K, kidney; RK, right kidney; and LK, left kidney. The American Journal of Human Genetics 2017 101, 123-129DOI: (10.1016/j.ajhg.2017.05.011) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 2 Evaluation of the Effect of the MYLK Variants Identified (A) Immunohistochemistry performed in control specimens with a specific MYLK antibody (1:100; Thermo Fisher Scientific) showed that MYLK is present in SMCs that constitute muscular structures of the intestine and the bladder, including muscularis mucosa, blood vessels, and circular and longitudinal muscles of the muscularis propria. Similar patterns and expression levels were present throughout all developmental stages included in this study. (B) MYLK is absent in the intestine and bladder of subject 1 (II-2 in Figure 1A). (C) H&E staining and immunostainings performed in specimens derived from control samples and subject 1 with specific antibodies against neurofilament (1:600; Monosan), c-Kit/CD117 (1:200; Cell Marque), tryptase (1:1,600; Dako), and ACTA2 (ready to use; Dako) showed no significant differences. (D) Splicing assays revealed impaired splicing of exon 23 of MYLK in subject 3 (II-5 in Figure 1A). SD6 and SA2 primers (Table S3) were used for evaluating transcripts produced by the wild-type (WT) vector, the mutant (Mut) vector containing the putative splice-site variant c.3985+5C>A, the empty vector (Empty), and untransfected cells (Un) according to a standard PCR protocol. The American Journal of Human Genetics 2017 101, 123-129DOI: (10.1016/j.ajhg.2017.05.011) Copyright © 2017 American Society of Human Genetics Terms and Conditions