Exome Sequencing Detects Uniparental Disomy of Chromosome 4 Revealing a LARP7 Pathogenic Variant Responsible for Alazami Syndrome: A Case Report

• Published in: American journal of medical genetics. Part A Vol. 197; no. 3; pp. e63891 - n/a
• Main Authors: Amélie, Buisine‐Sbraggia, Julien, Thevenon, Kevin, Yauy, Marie‐Emmanuelle, Naud, Jean‐Marc, Costa, Fanny, Dubois‐Teklali, Marjolaine, Willems, Klaus, Dieterich, Véronique, Satre, Charles, Coutton, Tanno, Pauline Le
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.03.2025; Wiley Subscription Services, Inc; Wiley
• Subjects: Alazami syndrome; Bioinformatics; Child, Preschool; Chromosome 4; Chromosomes; Chromosomes, Human, Pair 4 - genetics; Computer Science; Developmental Disabilities - genetics; Exome Sequencing; Genetic counseling; Genetics; Heterozygosity; Humans; Loss of heterozygosity; Loss of Heterozygosity - genetics; Male; neurodevelopmental disorders; Next-generation sequencing; Paternity; Phenotype; Polymorphism; Polymorphism, Single Nucleotide; Ribonucleoproteins - genetics; Single-nucleotide polymorphism; Uniparental disomy; Uniparental Disomy - genetics; Whole genome sequencing; exome sequencing; neurodevelopmental disorders; Alazami syndrome; uniparental disomy
• ISSN: 1552-4825; 1552-4833; 1552-4833
• DOI: 10.1002/ajmg.a.63891

ABSTRACT Alazami syndrome is an autosomal recessive disease characterized by global developmental delay, growth restriction, and distinctive facial features. Fewer than 50 individuals are currently reported with biallelic loss of function variants in LARP7. We report the case of a 3.5‐year‐old boy born from nonconsanguineous parents, presenting with syndromic global developmental delay. Exome sequencing identified a homozygous frameshift pathogenic variant in LARP7. Parental analysis failed to detect the variant in the paternal sample, although the father's biological paternity was confirmed. Targeted secondary bioinformatic analyses at the LARP7 locus suggested a 45 Mb loss of heterozygosity (LOH), further confirmed by a single nucleotide polymorphism array that identified four LOH regions on chromosome 4, including one encompassing LARP7. This LOH exposes the recessive LARP7 pathogenic variant, resulting in the manifestation of Alazami syndrome. To our knowledge, this is the first reported case of Alazami syndrome due to uniparental disomy (UPD). UPD is a rare cause of autosomal recessive disorders. Its identification is crucial for genetic counseling to adjust recurrence risk for siblings. This case highlights the effectiveness and usefulness of bioinformatics algorithms applied to next generation sequencing in detecting such events.