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A Novel Homozygous Frameshift Variant in DYM Causing Dyggve-Melchior-Clausen Syndrome in Pakistani Patients.

ABSTRACT: Background: Dyggve-Melchior-Clausen syndrome (DMC) is a skeletal dysplasia with associated defects of brain development and intelligence. The truncating pathogenic variants in DYM are the most frequent cause of DMC. Smith-McCort (SMC), another skeletal dysplasia, is also caused by non-synonymous DYM variants. Methods and Results: In the current study, we examined a Pakistani consanguineous family with three affected members. Clinical features like spondyloepimetaphyseal dysplasia, indicative of characteristic skeletal abnormalities, and intellectual disability were observed. Our male patients had microcephaly and coarse facial features while the female patient did not represent microcephaly or abnormal facies, which are significant features of DMC patients. Sanger sequencing identified a novel homozygous frameshift insertion (c.95_96insT, p.W33Lfs*14) in DYM, which likely leads to nonsense-mediated decay (NMD). Conclusion: The novel frameshift change verifies the fact that pathogenic variants in DYM are the most frequent cause of DMC.

SUBMITTER: Gaboon NEA

PROVIDER: S-EPMC7378890 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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A Novel Homozygous Frameshift Variant in DYM Causing Dyggve-Melchior-Clausen Syndrome in Pakistani Patients.

Gaboon Nagwa E A NEA Parveen Asia A Ahmad Khaled A KA Shuaib Taghreed T Al-Aama Jumana Y JY Abdelwehab Lereen L Arif Amina A Wasif Naveed N

Frontiers in pediatrics 20200716

Background: Dyggve-Melchior-Clausen syndrome (DMC) is a skeletal dysplasia with associated defects of brain development and intelligence. The truncating pathogenic variants in DYM are the most frequent cause of DMC. Smith-McCort (SMC), another skeletal dysplasia, is also caused by non-synonymous DYM variants. Methods and Results: In the current study, we examined a Pakistani consanguineous family with three affected members. Clinical features like spondyloepimetaphyse ...[more]

PMID: 32766185

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Project description:IntroductionDyggve-Melchior-Clausen (DMC) syndrome is a rare autosomal recessive type of skeletal dysplasia. It is characterized by the association of progressive spondyloepimetaphyseal dysplasia (SEMD), microcephaly, mental retardation (MR), and coarse facies. The radiographic appearance of generalized platyspondyly with double-humped end plates and the lace-like appearance of iliac crests are pathognomonic and distinctive of DMC syndrome. The disorder results from mutations in the DYM gene mapped in the 18q12-12.1 chromosomal region.Materials and methodsIn this report, we studied 15 Egyptian cases with DMC syndrome from nine unrelated families. We aimed to emphasize the characteristic clinical and radiological features in order to differentiate the condition from other SEMDs and mucopolysaccharidosis (MPS). Patients were subjected to detailed history taking, three-generation family pedigree analysis, complete physical examination, anthropometric measurements, quantitative estimation, and two-dimensional electrophoresis of glycosaminoglycans in the urine and measurement of α-l-iduronidase and galactose-6-sulfatase enzyme activities to exclude Hurler and Morquio diseases (MPS type I and MPS type IVA), respectively. Other investigations were carried out whenever indicated. All patients were the offspring of consanguineous apparently normal parents. Positive family history and similarly affected sibs were noted, confirming the autosomal recessive inheritance pattern of the syndrome. Short stature, microcephaly, variable degree of MR, and coarse facies were constant features. The frequency of characteristic orthopedic and radiological findings was reported. Orthopedic surgical intervention was carried out for two patients.ConclusionsThe study concluded that DMC syndrome may be more frequent in Egypt than previously thought, especially due to misdiagnosis. Characteristic facial dysmorphism, body habitus, and pathognomonic radiological signs suggest the diagnosis and differentiate it from other types of SEMDs and MPS for proper genetic counseling and management.

Dataset Information

A Novel Homozygous Frameshift Variant in DYM Causing Dyggve-Melchior-Clausen Syndrome in Pakistani Patients.

Publications

A Novel Homozygous Frameshift Variant in <i>DYM</i> Causing Dyggve-Melchior-Clausen Syndrome in Pakistani Patients.

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