TCEAL1 loss-of-function results in an X-linked dominant neurodevelopmental syndrome and drives the neurological disease trait in Xq22.2 deletions.
СтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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Hijazi Hadia, Reis Linda M, Pehlivan Davut, Bernstein Jonathan A, Muriello Michael, Syverson Erin, Bonner Devon, Estiar Mehrdad A, Gan-Or Ziv, Rouleau Guy A, Lyulcheva Ekaterina, Greenhalgh Lynn, Tessarech Marine, Colin Estelle, Guichet Agnès, Bonneau Dominique, van Jaarsveld R H, Lachmeijer A M A, Ruaud Lyse, Levy Jonathan, Tabet Anne-Claude, Ploski Rafal, Rydzanicz Małgorzata, Kępczyński Łukasz, Połatyńska Katarzyna, Li Yidan, Fatih Jawid M, Marafi Dana, Rosenfeld Jill A, Coban-Akdemir Zeynep, Bi Weimin, Gibbs Richard A, Hobson Grace M, Hunter Jill V, Carvalho Claudia M B, Posey Jennifer E, Semina Elena V, Lupski James R
Аннотация
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.