Kleefstra syndrome: Recurrence in siblings due to a paternal mosaic mutation

• Published in: American journal of medical genetics. Part A Vol. 185; no. 12; pp. 3877 - 3883
• Main Authors: Jobic, Florence, Lacot‐Leriche, Emilie, Piton, Amélie, Le Moing, Anne‐Gaëlle, Mathieu‐Dramard, Michèle, Costantini, Sara, Morin, Gilles, Jedraszak, Guillaume
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.12.2021; Wiley Subscription Services, Inc; Wiley
• Subjects: Abnormalities, Multiple - genetics; Abnormalities, Multiple - pathology; Adolescent; Adult; Autism; Children; Chromosome Deletion; Chromosomes, Human, Pair 9 - genetics; Comparative Genomic Hybridization; Craniofacial Abnormalities - complications; Craniofacial Abnormalities - genetics; Craniofacial Abnormalities - pathology; Enuresis; Female; Genetic Counseling; Genetic disorders; Genetic Predisposition to Disease; Heart Defects, Congenital - complications; Heart Defects, Congenital - genetics; Heart Defects, Congenital - pathology; Hereditary diseases; Hernia; High-Throughput Nucleotide Sequencing; Histone methyltransferase; Histone-Lysine N-Methyltransferase - genetics; Humans; Intellectual disabilities; Intellectual Disability - complications; Intellectual Disability - genetics; Intellectual Disability - pathology; Kleefstra syndrome; Life Sciences; Macrocephaly; Male; Megalencephaly - genetics; Megalencephaly - pathology; Mental disorders; mosaic; Mosaicism; Mutation; Phenotype; Phenotypes; Phenotyping; recurrence; sibling; Siblings; Young Adult; recurrence; mosaic; mutation; sibling; Kleefstra syndrome
• ISSN: 1552-4825; 1552-4833; 1552-4833
• DOI: 10.1002/ajmg.a.62448

Kleefstra syndrome (KS) is a rare autosomic dominant genetic disorder caused by euchromatic histone methyltransferase 1 (EHMT1) alterations. Patients mainly present with moderate to severe intellectual disability, a severe delay in/or absence of speech, autism spectrum disorder, childhood hypotonia, neuropsychiatric anomalies, and distinctive dysmorphic features. Here, we report the cases of a male and a female, two younger siblings of three, with asymptomatic parents. An EHMT1 new mutation was identified. Both presented with a typical core phenotype. Some specific features were noted, such as macrocephaly (previously reported) and enuresis (not yet described). Parental analysis identified the mutation in the mosaic state in the father. Reverse phenotyping enabled us to highlight the pauci phenotype features of inguinal hernia, azoospermia, and possible behavioral disorders. This allowed us to adapt his follow‐up and genetic counseling for the family. Our three reported cases provide a new description of KS with an intragenic EHMT1 mutation, whereas in the literature most reported cases have EHMT1 deletions. Moreover, in the areas of next‐generation sequencing and trio techniques with parental segregation, it is important to remain cautious about disregarding variants based on an autosomal recessive hypothesis.