TCEAL1 Loss-of-Function Results in an X-Linked Dominant Neurodevelopmental Syndrome and Drives the Neurological Disease Trait in Xq222 Deletions

Authors

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

Publication Date

12-1-2022

Journal

American Journal of Human Genetics

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

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

Comments

Supplementary Materials

PMID: 36368327