Compound Heterozygous Loss Of Function Variants In Myl9 In A Child With Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome

Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS), or "visceral myopathy," is a severe early onset disorder characterized by impaired muscle contractility in the bladder and intestines. Five genes are linked to MMIHS: primarilyACTG2, but alsoLMOD1,MYH11,MYLK, andMYL9. Here we describe a three-year-old girl with bilateral hydronephrosis diagnosed at 20 weeks gestation and congenital mydriasis (both of which have been previously observed among individuals with MMIHS). A clinical diagnosis of MMIHS was made based upon the presence of megacystis, lack of urinary bladder peristalsis, and intestinal pseudo-obstruction. After initial testing ofACTG2was negative, further sequencing and deletion/duplication testing was performed on theLMOD1,MYH11,MYLK, andMYL9genes. We identified two heterozygous loss of function variants inMYL9: an exon 4 deletion and a nine base pair deletion that removes the canonical splicing donor site at exon 2 (NM_006097.5:c.184+2_184+10del). Parental testing confirmed these variants to bein transin our proband. To our knowledge, only one other individual with MMIHS has biallelic mutations inMYL9(a homozygous deletion encompassing exon 4). We suggestMYL9be targeted on genetic testing panels for MMIHS, smooth muscle myopathies, and cardiovascular phenotypes.