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Mol Autism. 2019 Oct 22;10:35. doi: 10.1186/s13229-019-0286-0. eCollection 2019.

Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism.

Author information

1Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, Qatar.
2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX USA.
3Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX USA.
4Laboratoires de Diagnostic Génétique, Unité de génétique moléculaire, Nouvel Hôpital Civil, Strasbourg Cedex, France.
5Section of Reproductive Endocrinology, Infertility & Genetics, Department of Obstetrics & Gynecology, Augusta University, Augusta, GA USA.
Baylor Genetic Laboratories, Houston, TX USA.
7Kennedy Krieger Institute, Baltimore, MD USA.
8Department of Medical Genetics, Lyon University Hospital, Lyon, France.
9Department of Pediatric Neurology, Lyon University Hospital, Lyon, France.
10Équipe Génétique des Anomalies du Développement (GAD), INSERM, Dijon, France.
Centre de Génétique, CHU Dijon Bourgogne, Dijon, France.
Service de Génétique Clinique, CHU Robert Debré, Paris, France.
13Clinical Genetics, Stanford Children's Health at CPMC, San Francisco, CA USA.
14GeneDx, Gaithersburg, MD USA.
15Max Delbrück Center (MDC) for Molecular Medicine, Berlin, Germany.
16Diabetes Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University, Doha, Qatar.
17Department of Neuroscience and Regenerative Medicine, Augusta University, Augusta, GA USA.
18Department of Statistics and Actuarial Science, Northern Illinois University, DeKalb, IL USA.
19Department of Animal Science, Division of Applied Life Science (BK21plus), Gyeongsang National University, Jinju, Korea.
20Pediatric Medical Genetics, Children's Hospital of Pittsburgh, Pittsburgh, PA USA.
21Department of Biology, Chungnam National University, Daejeon, Korea.



PHF21A has been associated with intellectual disability and craniofacial anomalies based on its deletion in the Potocki-Shaffer syndrome region at 11p11.2 and its disruption in three patients with balanced translocations. In addition, three patients with de novo truncating mutations in PHF21A were reported recently. Here, we analyze genomic data from seven unrelated individuals with mutations in PHF21A and provide detailed clinical descriptions, further expanding the phenotype associated with PHF21A haploinsufficiency.


Diagnostic trio whole exome sequencing, Sanger sequencing, use of GeneMatcher, targeted gene panel sequencing, and MiSeq sequencing techniques were used to identify and confirm variants. RT-qPCR was used to measure the normal expression pattern of PHF21A in multiple human tissues including 13 different brain tissues. Protein-DNA modeling was performed to substantiate the pathogenicity of the missense mutation.


We have identified seven heterozygous coding mutations, among which six are de novo (not maternal in one). Mutations include four frameshifts, one nonsense mutation in two patients, and one heterozygous missense mutation in the AT Hook domain, predicted to be deleterious and likely to cause loss of PHF21A function. We also found a new C-terminal domain composed of an intrinsically disordered region. This domain is truncated in six patients and thus likely to play an important role in the function of PHF21A, suggesting that haploinsufficiency is the likely underlying mechanism in the phenotype of seven patients. Our results extend the phenotypic spectrum of PHF21A mutations by adding autism spectrum disorder, epilepsy, hypotonia, and neurobehavioral problems. Furthermore, PHF21A is highly expressed in the human fetal brain, which is consistent with the neurodevelopmental phenotype.


Deleterious nonsense, frameshift, and missense mutations disrupting the AT Hook domain and/or an intrinsically disordered region in PHF21A were found to be associated with autism spectrum disorder, epilepsy, hypotonia, neurobehavioral problems, tapering fingers, clinodactyly, and syndactyly, in addition to intellectual disability and craniofacial anomalies. This suggests that PHF21A is involved in autism spectrum disorder and intellectual disability, and its haploinsufficiency causes a diverse neurological phenotype.


AT Hook domain; Autism spectrum disorder (ASD); BHC80; Intellectual disability (ID); Intrinsically disordered region (IDR); KDM1A; Neurodevelopmental disorders; PHF21A; Potocki-Shaffer syndrome (PSS)

Conflict of interest statement

Competing interestsThe Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing conducted by Baylor Genetics Laboratory. Dianalee McKnight and Erin Torti are employees of GeneDx, Inc., a wholly owned subsidiary of OPKO Health, Inc. The other authors declare that they have no competing interests.

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