Challenging Genetic Diagnosis in Siblings With Primordial Dwarfism, Muscle Wasting, Osteogenesis Imperfecta,...

Three siblings of consanguineous Pakistani parents have primordial dwarfism with microcephaly, failure to thrive, delayed developmental milestones, thin and lean physique, dysplastic limb joints, ectodermal anomalies, and craniofacial anomalies including dolichocephaly, micrognathia, and irregular dentition. Variable findings are muscular dystrophy and osteogenesis imperfecta. We hypothesized a novel syndrome and launched a disease gene search. At the gene locus identified by single-nucleotide polymorphism-based linkage mapping, genome sequencing detected a very rare intergenic variant g.132766396A>G (chromosome 12) in a regulatory element in ANKLE2, a gene related to microcephaly. As the mutation did not explain all clinical features, we analyzed patient exome files individually and found six very rare homozygous mutations in CENPE, POC1A, PCNT, TMEM38B, and TMEM43. The patients had different combinations of those variants, which explained all phenotypes in two of them, except for thin skin. Such formidable genetic heterogeneity in siblings with similar phenotypes and numerous mutations demonstrates an unusual difficulty in establishing genetic diagnosis and raises caution for seemingly "novel syndromes." A patient with additional osteogenesis imperfecta was homozygous for the first missense disease-causing homozygous TMEM38B mutation to date. The patient's older sister was nonpenetrant. The patient with muscular dystrophy had a homozygous mutation in TMEM43 related to dominant Emery-Dreifuss muscular dystrophy 7.