Speaker
Description
Background: Mandibuloacral dysplasia (MAD) is a progeria disease with postnatal age of manifestation, and clinical signs start manifesting by 2 years. Accelerated ageing, skeletal abnormalities and lipodystrophy characterise the condition. MAD type (MADA) and MAD type B (MADB) result from homozygous or compound heterozygous mutations in LMNA and ZMPSTE24 genes, respectively. The current study sought to decipher the genetic aetiology of progeria in a Ghanaian multiplex family.
Methods: CT scan, echocardiogram and X-ray assessed brain, heart, lungs and bones of the affected individuals. Due to the genetic heterogeneity of progeria, we opted to undertake whole-exome sequencing (WES) on DNA samples obtained from all 7 individuals in a multiplex family. WES was undertaken employing Illumina HiSeq at 100X, using GRCh38. Sentieon workflow was utilised for quality control checks, read alignment and variant calling. Ensembl VEP was utilised to annotate variants, and variant prioritisation using guidelines on variant classification by the American College of Medical Genetics and Genomics (ACMG).
Results: Two affected individuals in the family presented with accelerated ageing, short stature, micrognathia with bilateral mandibular condylar aplasia, dental overcrowding, alopecia, prominent eyes, narrow shoulders with absent clavicles, bilateral brachydactyly and finger contracture, acro-osteolysis of distal phalanges, variegated skin pigmentation, delayed closure of cranial sutures, and lipodystrophy at joints. WES revealed a recurrent homozygous mutation (ENST00000368300.9:c.1579C>T, p.Arg527Cys) in LMNA gene for both affected males of the family. All but one clinically unaffected individuals, including third-degree consanguineous parents, were heterozygous for the variant.
Conclusions: A recurrent homozygous LMNA mutation causes autosomal recessive MADA.