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. 2020 Jan;182(1):38-52.
doi: 10.1002/ajmg.a.61380. Epub 2019 Nov 29.

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

Nurit Assia Batzir  1   2 , Jennifer E Posey  1 , Xiaofei Song  1 , Zeynep Coban Akdemir  1 , Jill A Rosenfeld  1 , Chester W Brown  3   4 , Emily Chen  5 , Shannon G Holtrop  3 , Elizabeth Mizerik  1   2 , Margarita Nieto Moreno  6   7 , Katelyn Payne  8 , Annick Raas-Rothschild  9   10 , Richard Scott  11 , Hilary J Vernon  12 , Neda Zadeh  13   14 ; Baylor-Hopkins Center for Mendelian Genomics  1 ; James R Lupski  1   2   15   16 , V Reid Sutton  1   2
Affiliations

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

Nurit Assia Batzir et al. Am J Med Genet A. 2020 Jan.

Abstract

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.

Keywords: POGZ; autism; developmental delay; intellectual disability; speech delay.

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Conflict of interest statement

Conflict of Interest:

Baylor College of Medicine (BCM) and Miraca Holdings Inc. have formed a joint venture with shared ownership and governance of BG, formerly the Baylor Miraca Genetics Laboratories (BMGL), which performs clinical exome sequencing and chromosomal microarray analysis for genome-wide detection of copy number variants. J.R.L. serves on the Scientific Advisory Board of BG. J.R.L. has stock ownership in 23andMe, is a paid consultant for Regeneron Pharmaceuticals, and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases and bacterial genomic fingerprinting. V.R.S serves on the medical advisory board of the White-Sutton Syndrome Foundation. The other authors declare no conflict of interest.

Figures

Figure 1.
Figure 1.
Schematic representation of the POGZ protein and POGZ gene. Pathogenic variants in the present study shown above the exon structure and variants previously reported in the literature shown below. Black font—frameshift or nonsense variants. Purple font—splice variants. Red font—missense variants. Triangles mark additional reports of the same variant
Figure 2.
Figure 2.
Individuals from the study cohort. (a) PT5, 1 year. (b) PT5, 3.5 years. (c) PT15, 1.5 years. (d) PT15, 6 years. (e, f) PT8, 4 years. (g) PT18, 2 years. (h) PT21, age 10 months. (i) PT7, age unknown. (j) PT7, 3 years. (k) PT13, 4 months. (l) PT10, 14.5 years
Figure 3.
Figure 3.
Developmental milestones in the cohort. Bar plots represent different milestones in the gross motor, fine motor and language categories. Dashed lines mark age when 90% of children have achieved the milestone based on Denver II Developmental Scale (Frankenburg, Dodds, Archer, Shapiro, & Bresnick, 1992). Xs mark age at report when milestone was not achieved
See this image and copyright information in PMC

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