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Diagnostic screening identifies a wide range of mutations involving the SHOX gene, including a common 47.5?kb deletion 160?kb downstream with a variable phenotypic effect

Diagnostic screening identifies a wide range of mutations involving the SHOX gene, including a common 47.5?kb deletion 160?kb downstream with a variable phenotypic effect
Diagnostic screening identifies a wide range of mutations involving the SHOX gene, including a common 47.5?kb deletion 160?kb downstream with a variable phenotypic effect
Léri–Weill dyschondrosteosis (LWD) results from heterozygous mutations of the SHOX gene, with homozygosity or compound heterozygosity resulting in the more severe form, Langer mesomelic dysplasia (LMD). These mutations typically take the form of whole or partial gene deletions, point mutations within the coding sequence, or large (>100?kb) 3? deletions of downstream regulatory elements. We have analyzed the coding sequence of the SHOX gene and its downstream regulatory regions in a cohort of 377 individuals referred with symptoms of LWD, LMD or short stature. A causative mutation was identified in 68% of the probands with LWD or LMD (91/134). In addition, a 47.5?kb deletion was found 160?kb downstream of the SHOX gene in 17 of the 377 patients (12% of the LWD referrals, 4.5% of all referrals). In 14 of these 17 patients, this was the only potentially causative abnormality detected (13 had symptoms consistent with LWD and one had short stature only), but the other three 47.5?kb deletions were found in patients with an additional causative SHOX mutation (with symptoms of LWD rather than LMD). Parental samples were available on 14/17 of these families, and analysis of these showed a more variable phenotype ranging from apparently unaffected to LWD. Breakpoint sequence analysis has shown that the 47.5?kb deletion is identical in all 17 patients, most likely due to an ancient founder mutation rather than recurrence. This deletion was not seen in 471 normal controls (P?<?0.0001), providing further evidence for a phenotypic effect, albeit one with variable penetration.
SHOX, deletions, duplications, point mutations
1552-4825
1329-1338
Bunyan, David J.
dd9134b9-f889-44cc-83cc-a41fc5d74d69
Baker, Kevin R.
68027548-d885-48f8-99f7-946cc2062410
Harvey, John F.
b27b83e2-c681-4a87-9ce9-7686fc1bba36
Thomas, N. Simon
1a601957-288d-4f12-a9f7-4f4279b7f9b3
Bunyan, David J.
dd9134b9-f889-44cc-83cc-a41fc5d74d69
Baker, Kevin R.
68027548-d885-48f8-99f7-946cc2062410
Harvey, John F.
b27b83e2-c681-4a87-9ce9-7686fc1bba36
Thomas, N. Simon
1a601957-288d-4f12-a9f7-4f4279b7f9b3

Bunyan, David J., Baker, Kevin R., Harvey, John F. and Thomas, N. Simon (2013) Diagnostic screening identifies a wide range of mutations involving the SHOX gene, including a common 47.5?kb deletion 160?kb downstream with a variable phenotypic effect. American Journal of Medical Genetics: Part A, 161 (6), 1329-1338. (doi:10.1002/ajmg.a.35919). (PMID:23636926)

Record type: Article

Abstract

Léri–Weill dyschondrosteosis (LWD) results from heterozygous mutations of the SHOX gene, with homozygosity or compound heterozygosity resulting in the more severe form, Langer mesomelic dysplasia (LMD). These mutations typically take the form of whole or partial gene deletions, point mutations within the coding sequence, or large (>100?kb) 3? deletions of downstream regulatory elements. We have analyzed the coding sequence of the SHOX gene and its downstream regulatory regions in a cohort of 377 individuals referred with symptoms of LWD, LMD or short stature. A causative mutation was identified in 68% of the probands with LWD or LMD (91/134). In addition, a 47.5?kb deletion was found 160?kb downstream of the SHOX gene in 17 of the 377 patients (12% of the LWD referrals, 4.5% of all referrals). In 14 of these 17 patients, this was the only potentially causative abnormality detected (13 had symptoms consistent with LWD and one had short stature only), but the other three 47.5?kb deletions were found in patients with an additional causative SHOX mutation (with symptoms of LWD rather than LMD). Parental samples were available on 14/17 of these families, and analysis of these showed a more variable phenotype ranging from apparently unaffected to LWD. Breakpoint sequence analysis has shown that the 47.5?kb deletion is identical in all 17 patients, most likely due to an ancient founder mutation rather than recurrence. This deletion was not seen in 471 normal controls (P?<?0.0001), providing further evidence for a phenotypic effect, albeit one with variable penetration.

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More information

e-pub ahead of print date: 1 May 2013
Published date: June 2013
Keywords: SHOX, deletions, duplications, point mutations
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 353023
URI: https://eprints.soton.ac.uk/id/eprint/353023
ISSN: 1552-4825
PURE UUID: 294cdd98-53b6-40bc-a098-18f8e105dd1b

Catalogue record

Date deposited: 23 Oct 2013 08:39
Last modified: 16 Jul 2019 21:32

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