Can leaky splicing and evasion of premature termination codon surveillance contribute to the phenotypic variability in Alkuraya-Kucinskas syndrome?

Chin, Hui-Lin; Lin, Susan; Dalmann, Joshua; Modi, Bhavi P.; Alderman, Emily; Salman, Areesha; Bel, Kate L. Del; Lehman, Anna; Turvey, Stuart E.; Boerkoel, Cornelius F.

doi:10.1016/j.ejmg.2022.104427

Cited by 3 publications

(2 citation statements)

References 13 publications

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“…The phenotypic variability of patients analysed here can be attributed to the inherent leakiness of splicing, a feature of the stochastic variation resulting from competition between acceptor sites of the pseudoexon and the downstream exon in affinity for binding of the spliceosome ( Anna and Monika, 2018 ; Chin et al, 2022 ). This phenomenon has been characterized previously in other diseases, such as disease severity in cystic fibrosis in patients correlating with the degree of intron 19 pseudoexon inclusion resulting from the CFTR c.3718-2477C>T variant ( Sobczyńska-Tomaszewska et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

Deep intronic variant causes aberrant splicing of ATP7A in a family with a variable occipital horn syndrome phenotype

Harkness,

Thomas,

Urquhart

et al. 2024

European Journal of Medical Genetics

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Section: Discussionmentioning

confidence: 99%

Deep intronic variant causes aberrant splicing of ATP7A in a family with a variable occipital horn syndrome phenotype

Harkness,

Thomas,

Urquhart

et al. 2024

European Journal of Medical Genetics

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“…Nevertheless H, AS, and LL of heterozygotes predominantly cluster in the lower normal range when compared to wild-type family members. While leaky splice-site variants have been proven to contribute to phenotypic variation in other monogenetic human diseases [ 19 , 20 , 21 , 22 , 23 ], it remains unclear if this non-disease-relevant trend can be linked to the identified leaky c.544+5G>C SHOX splice-site variant, due to the limited sample size within this single pedigree and the high number of genes contributing to human growth. SHOX is known as a major growth gene that controls bone maturation, chondrocyte differentiation and proliferation, cellular growth arrest, and apoptosis by transcriptional regulation of its direct target genes FGFR3 , NPPB , and CTGF [ 2 , 24 , 25 , 26 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

Leri–Weill Dyschondrosteosis Caused by a Leaky Homozygous SHOX Splice-Site Variant

Vodopiutz

Steurer

Haufler

et al. 2023

Genes

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SHOX deficiency is a common genetic cause of short stature of variable degree. SHOX haploinsufficiency causes Leri–Weill dyschondrosteosis (LWD) as well as nonspecific short stature. SHOX haploinsufficiency is known to result from heterozygous loss-of-function variants with pseudo-autosomal dominant inheritance, while biallelic SHOX loss-of-function variants cause the more severe skeletal dysplasia, Langer mesomelic dyschondrosteosis (LMD). Here we report for the first time the pseudo-autosomal recessive inheritance of LWD in two siblings caused by a novel homozygous non-canonical, leaky splice-site variant in intron 3 of SHOX: c.544+5G>C. Transcript analyses in patient-derived fibroblasts showed homozygous patients to produce approximately equal amounts of normally spliced mRNA and mRNA with the abnormal retention of intron 3 and containing a premature stop codon (p.Val183Glyfs*31). The aberrant transcript was shown to undergo nonsense-mediated mRNA decay, and thus resulting in SHOX haploinsufficiency in the homozygous patient. Six healthy relatives who are of normal height are heterozygous for this variant and fibroblasts from a heterozygote for the c.544+5G>C variant produced wild-type transcript amounts comparable to healthy control. The unique situation reported here highlights the fact that the dosage of SHOX determines the clinical phenotype rather than the Mendelian inheritance pattern of SHOX variants. This study extends the molecular and inheritance spectrum of SHOX deficiency disorder and highlights the importance of functional testing of SHOX variants of unknown significance in order to allow appropriate counseling and precision medicine for each family individual.

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Partial loss of desmin expression due to a leaky splice site variant in the human DES gene is associated with neuromuscular transmission defects

Polavarapu,

O'Neil,

Thompson

et al. 2024

Neuromuscular Disorders

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Can leaky splicing and evasion of premature termination codon surveillance contribute to the phenotypic variability in Alkuraya-Kucinskas syndrome?

Cited by 3 publications

References 13 publications

Deep intronic variant causes aberrant splicing of ATP7A in a family with a variable occipital horn syndrome phenotype

Deep intronic variant causes aberrant splicing of ATP7A in a family with a variable occipital horn syndrome phenotype

Leri–Weill Dyschondrosteosis Caused by a Leaky Homozygous SHOX Splice-Site Variant

Partial loss of desmin expression due to a leaky splice site variant in the human DES gene is associated with neuromuscular transmission defects

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