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Biallelic ZNF407 mutations in a neurodevelopmental disorder with ID, short stature and variable microcephaly, hypotonia, ocular anomalies and facial dysmorphism

Journal of Human Genetics volume 65, pages 1115–1123 (2020)Cite this article

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Abstract

We describe five members of a consanguineous Pakistani family (Family I) plus two affected children from families of different ethnic origins presenting with neurodevelopmental disorders with overlapping features. All affected individuals from families have intellectual disability (ID), ranging from mild to profound, and reduced motor and cognitive skills plus variable features including short stature, microcephaly, developmental delay, hypotonia, dysarthria, deafness, visual problems, enuresis, encopresis, behavioural anomalies, delayed pubertal onset and facial dysmorphism. We first mapped the disease locus in the large family (Family I), and by exome sequencing identified homozygous ZNF407 c.2814_2816dup (p.Val939dup) in four affected members where DNA samples were available. By exome sequencing we detected homozygous c.2405G>T (p.Gly802Val) in the affected member of Family II and compound heterozygous variants c.2884C>G (p.Arg962Gly) and c.3642G>C (p.Lys1214Asn) in the affected member of Family III. Homozygous c.5054C>G (p.Ser1685Trp) has been reported in two brothers with an ID syndrome. Affected individuals we present did not exhibit synophrys, midface hypoplasia, kyphosis, 5th finger camptodactyly, short 4th metatarsals or limited knee mobility observed in the reported family.

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Acknowledgements

We thank the participants for their cooperation and Dr. Michelle Morrow for critical reading of the paper. This study was supported by the Scientific and Technological Research Council of Turkey (114Z829 to AT) and URF-QAU Pakistan (2014–2015 to SM).

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Author notes

  1. These authors contributed equally: Qandeel Zahra, Çağla Çakmak, Mine Koprulu

Authors and Affiliations

  1. Human Genetics Program, Department of Zoology, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan

    Qandeel Zahra, Muhammad Shuaib & Sajid Malik

  2. Department of Molecular Biology and Genetics, Boğaziçi University, Istanbul, Turkey

    Çağla Çakmak, Mine Koprulu & Aslıhan Tolun

  3. Department of Molecular Biology and Genetics, Istanbul Technical University, Istanbul, Turkey

    Mine Koprulu & Aslıhan Tolun

  4. McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Nara Sobreira

  5. Departments of Neurology and Pediatrics, University of Connecticut School of Medicine and Connecticut Children’s Medical Center, Farmington, CT, USA

    Louisa Kalsner

  6. Division of Genetics, Department of Morphology and Genetics, Universidade Federal de Sao Paulo, Sao Paulo, Brazil

    Joselito Sobreira

  7. GeneDx, Gaithersburg, MD, USA

    Maria J. Guillen Sacoto

Authors
  1. Qandeel Zahra
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  2. Çağla Çakmak
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  4. Muhammad Shuaib
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  8. Maria J. Guillen Sacoto
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Contributions

QZ, MS, SM, LK and JS performed clinical evaluations; ÇÇ, AT, MJGS and NS performed genetic studies and analysed data; MK performed bioinformatics analysis; AT, SM and MK wrote the paper.

Corresponding authors

Correspondence to Sajid Malik or Aslıhan Tolun.

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Conflict of interest

MJGS is an employee of GeneDx, Inc. Other authors declare that they have no conflicts of interest.

Ethical approval

The study protocol was approved by the Ethical Review Committee of Quaid-i-Azam University (DAS/12-HG-07) and the Istanbul Technical University Human Research Ethical Review Board (MBG.22/2014).

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Zahra, Q., Çakmak, Ç., Koprulu, M. et al. Biallelic ZNF407 mutations in a neurodevelopmental disorder with ID, short stature and variable microcephaly, hypotonia, ocular anomalies and facial dysmorphism. J Hum Genet 65, 1115–1123 (2020). https://doi.org/10.1038/s10038-020-0812-0

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