Phenotypic expansion of POGZ‐related intellectual disability syndrome (White‐Sutton syndrome)

• Published in: American journal of medical genetics. Part A Vol. 182; no. 1; pp. 38 - 52
• Main Authors: Assia Batzir, Nurit, Posey, Jennifer E., Song, Xiaofei, Akdemir, Zeynep Coban, Rosenfeld, Jill A., Brown, Chester W., Chen, Emily, Holtrop, Shannon G., Mizerik, Elizabeth, Nieto Moreno, Margarita, Payne, Katelyn, Raas‐Rothschild, Annick, Scott, Richard, Vernon, Hilary J., Zadeh, Neda, Lupski, James R., Sutton, V. Reid
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.01.2020; Wiley Subscription Services, Inc
• Subjects: Adolescent; Adult; Apnea; Autism; Autistic Disorder - genetics; Autistic Disorder - pathology; Body mass index; Child; Child, Preschool; developmental delay; Exome - genetics; Female; Gait; Genetic disorders; Hearing loss; Heterozygote; Humans; Hypoplasia; Infant; Intellectual disabilities; intellectual disability; Intellectual Disability - epidemiology; Intellectual Disability - genetics; Intellectual Disability - pathology; Language Development Disorders - genetics; Language Development Disorders - pathology; Male; Microcephaly - genetics; Microcephaly - pathology; Microencephaly; Middle Aged; Mutation - genetics; Phenotype; Phenotypes; POGZ; Sleep; Sleep disorders; speech delay; Transposases - genetics; Whole Exome Sequencing; Young Adult; speech delay; developmental delay; autism; intellectual disability; POGZ
• ISSN: 1552-4825; 1552-4833
• DOI: 10.1002/ajmg.a.61380

White‐Sutton syndrome (WHSUS) is a recently‐identified genetic disorder resulting from de novo heterozygous pathogenic variants in POGZ. Thus far, over 50 individuals have been reported worldwide, however phenotypic characterization and data regarding the natural history are still incomplete. Here we report the clinical features of 22 individuals with 21 unique loss of function POGZ variants. We observed a broad spectrum of intellectual disability and/or developmental delay with or without autism, and speech delay in all individuals. Other common problems included ocular abnormalities, hearing loss and gait abnormalities. A validated sleep disordered breathing questionnaire identified symptoms of obstructive sleep apnea in 4/12 (33%) individuals. A higher‐than‐expected proportion of cases also had gastrointestinal phenotypes, both functional and anatomical, as well as genitourinary anomalies. In line with previous publications, we observed an increased body mass index (BMI) z‐score compared to the general population (mean 0.59, median 0.9; p 0.0253). Common facial features included microcephaly, broad forehead, midface hypoplasia, triangular mouth, broad nasal root and flat nasal bridge. Analysis of the Baylor Genetics clinical laboratory database revealed that POGZ variants were implicated in approximately 0.14% of cases who underwent clinical exome sequencing for neurological indications with or without involvement of other body systems. This study describes a greater allelic series and expands the phenotypic spectrum of this new syndromic form of intellectual disability and autism.