4.7 Article

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

期刊

AMERICAN JOURNAL OF HUMAN GENETICS
卷 109, 期 12, 页码 2270-2282

出版社

CELL PRESS
DOI: 10.1016/j.ajhg.2022.10.007

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资金

  1. US National Human Genome Research Institute (NHGRI)/National Heart, Lung, and Blood Institute (NHLBI) [UM1 HG006542]
  2. US National Institute of Neurological Disorders and Stroke (NINDS) [R01 NS058529, R35 NS105078]
  3. National Institute of General Medical Sciences (NIGMS) [R01 GM106373]
  4. NHGRI [U01 HG011758, K08 HG008986]
  5. NIGMS [T32 GM007526-42]
  6. Clinical and Translational Science Award (CTSA) program [R01EY025718, EY015518, 1UL1RR031973]
  7. International Rett Syndrome Foundation [3701-1]

向作者/读者索取更多资源

This study confirms that loss of function of TCEAL1 causes a neurological rare disease trait that overlaps with the EONDT phenotype in females with Xq22 deletion, including hypotonia, intellectual disability, neurobehavioral abnormalities, and dysmorphic facial features.
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 hy-potonia, 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 contig-uous 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, sei-zures, and structural brain anomalies. An additional maternally inherited hemizygous missense allele of uncertain significance was iden-tified 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.

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