TCEAL1 loss-of-function results in an X-linked dominant neurodevelopmental syndrome and drives the neurological disease trait in Xq22.2 deletions

Hadia Hijazi; Linda M Reis; Davut Pehlivan; Jonathan A Bernstein; Michael Muriello; Erin Syverson; Devon Bonner; Mehrdad A Estiar; Ziv Gan-Or; Guy A Rouleau; Ekaterina Lyulcheva; Lynn Greenhalgh; Marine Tessarech; Estelle Colin; Agnès Guichet; Dominique Bonneau; R H van Jaarsveld; A M A Lachmeijer; Lyse Ruaud; Jonathan Levy; Anne-Claude Tabet; Rafal Ploski; Małgorzata Rydzanicz; Łukasz Kępczyński; Katarzyna Połatyńska; Yidan Li; Jawid M Fatih; Dana Marafi; Jill A Rosenfeld; Zeynep Coban-Akdemir; Weimin Bi; Richard A Gibbs; Grace M Hobson; Jill V Hunter; Claudia M B Carvalho; Jennifer E Posey; Elena V Semina; James R Lupski

doi:10.1016/j.ajhg.2022.10.007

TCEAL1 loss-of-function results in an X-linked dominant neurodevelopmental syndrome and drives the neurological disease trait in Xq22.2 deletions

Am J Hum Genet. 2022 Dec 1;109(12):2270-2282. doi: 10.1016/j.ajhg.2022.10.007. Epub 2022 Nov 10.

Authors

Hadia Hijazi¹, Linda M Reis², Davut Pehlivan³, Jonathan A Bernstein⁴, Michael Muriello², Erin Syverson², Devon Bonner⁴, Mehrdad A Estiar⁵, Ziv Gan-Or⁶, Guy A Rouleau⁶, Ekaterina Lyulcheva⁷, Lynn Greenhalgh⁷, Marine Tessarech⁸, Estelle Colin⁸, Agnès Guichet⁸, Dominique Bonneau⁸, R H van Jaarsveld⁹, A M A Lachmeijer⁹, Lyse Ruaud¹⁰, Jonathan Levy¹¹, Anne-Claude Tabet¹¹, Rafal Ploski¹², Małgorzata Rydzanicz¹², Łukasz Kępczyński¹³, Katarzyna Połatyńska¹⁴, Yidan Li¹, Jawid M Fatih¹, Dana Marafi¹, Jill A Rosenfeld¹⁵, Zeynep Coban-Akdemir¹, Weimin Bi¹⁵, Richard A Gibbs¹⁶, Grace M Hobson¹⁷, Jill V Hunter¹⁸, Claudia M B Carvalho¹, Jennifer E Posey¹, Elena V Semina¹⁹, James R Lupski²⁰

Affiliations

¹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
² Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin and Children's Wisconsin, Milwaukee, WI, USA.
³ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, USA.
⁴ Department of Pediatrics, Division of Medical Genetics, Stanford School of Medicine, Stanford, CA, USA.
⁵ Department of Human Genetics, McGill University, Montreal, QC, Canada; The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, QC, Canada.
⁶ Department of Human Genetics, McGill University, Montreal, QC, Canada; The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, QC, Canada; Department of Neurology & Neurosurgery, McGill University, Montreal, QC, Canada.
⁷ Liverpool Centre for Genomic Medicine, Liverpool Women's Hospital, Liverpool, UK.
⁸ Department of Medical Genetics, Angers University Hospital, Angers, France; Mitovasc Unit, UMR CNRS 6015-INSERM 1083, University of Angers, Angers, France.
⁹ Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
¹⁰ INSERM UMR1141, Neurodiderot, University of Paris, 75019 Paris, France; APHP.Nord, Robert Debré University Hospital, Department of Genetics, 75019 Paris, France.
¹¹ APHP.Nord, Robert Debré University Hospital, Department of Genetics, 75019 Paris, France.
¹² Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland.
¹³ Department of Genetics, Polish Mother's Memorial Hospital - Research Institute, Łódź, Poland.
¹⁴ Department of Developmental Neurology an Epileptology, Polish Mother's Memorial Hospital - Research Institute, Łódź, Poland.
¹⁵ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Baylor Genetics, Houston, TX, USA.
¹⁶ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
¹⁷ Department of Research, Nemours Children's Health, Wilmington, DE, USA.
¹⁸ E.B. Singleton Department of Pediatric Radiology, Texas Children's Hospital, Houston, TX, USA.
¹⁹ Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin and Children's Wisconsin, Milwaukee, WI, USA; Departments of Ophthalmology and Visual Sciences and Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA. Electronic address: [email protected].
²⁰ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA. Electronic address: [email protected].

Abstract

An Xq22.2 region upstream of PLP1 has been proposed to underly a neurological disease trait when deleted in 46,XX females. Deletion mapping revealed that heterozygous deletions encompassing the smallest region of overlap (SRO) spanning six Xq22.2 genes (BEX3, RAB40A, TCEAL4, TCEAL3, TCEAL1, and MORF4L2) associate with an early-onset neurological disease trait (EONDT) consisting of hypotonia, intellectual disability, neurobehavioral abnormalities, and dysmorphic facial features. None of the genes within the SRO have been associated with monogenic disease in OMIM. Through local and international collaborations facilitated by GeneMatcher and Matchmaker Exchange, we have identified and herein report seven de novo variants involving TCEAL1 in seven unrelated families: three hemizygous truncating alleles; one hemizygous missense allele; one heterozygous TCEAL1 full gene deletion; one heterozygous contiguous deletion of TCEAL1, TCEAL3, and TCEAL4; and one heterozygous frameshift variant allele. Variants were identified through exome or genome sequencing with trio analysis or through chromosomal microarray. Comparison with previously reported Xq22 deletions encompassing TCEAL1 identified a more-defined syndrome consisting of hypotonia, abnormal gait, developmental delay/intellectual disability especially affecting expressive language, autistic-like behavior, and mildly dysmorphic facial features. Additional features include strabismus, refractive errors, variable nystagmus, gastroesophageal reflux, constipation, dysmotility, recurrent infections, seizures, and structural brain anomalies. An additional maternally inherited hemizygous missense allele of uncertain significance was identified in a male with hypertonia and spasticity without syndromic features. These data provide evidence that TCEAL1 loss of function causes a neurological rare disease trait involving significant neurological impairment with features overlapping the EONDT phenotype in females with the Xq22 deletion.

Keywords: DD/ID; EONDT; NDD; TCEAL1; X-linked disease trait; Xq22.2 deletion; developmental delay/intellectual disability; early-onset neurological disease trait; hypotonia; neurodevelopmental disorder.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Autistic Disorder* / genetics
Female
Humans
Intellectual Disability* / complications
Intellectual Disability* / genetics
Male
Muscle Hypotonia / complications
Muscle Hypotonia / genetics
Phenotype
Syndrome
Transcription Factors / genetics

Substances

MORF4L2 protein, human
Transcription Factors
TCEAL1 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding