Microcephalic primordial dwarfism with predominant Meier-Gorlin phenotype, ichthyosis, and multiple joint deformities-Further expansion of DONSON Cell Cycle-opathy phenotypic spectrum.

We report a patient with microcephalic primordial dwarfism with predominant Meier-Gorlin syndrome phenotype with ichthyosis and disabling multiple joint deformities in addition to classic features of the syndrome. The patient was a 10.5-year-old girl referred in view of short stature, joint deformities, and facial dysmorphism. There was history of intrauterine growth restriction and collodion like skin abnormality at birth. She had normal developmental milestones and intellect. On clinical evaluation, anthropometry was suggestive of proportionate short stature and microcephaly. There was abnormal posture due to spine and peripheral joint deformities, along with ichthyosis, facial, and digital dysmorphism. Skeletal radiographs showed radial subluxation, acetabular dysplasia and hip dislocation, bilateral knee joint dislocation, absent patellae, slender long bones with delayed bone age, and subluxation of small joints of hands and feet. Work up for metabolic bone disease and peripheral blood karyotype was normal. Whole exome sequencing revealed a pathogenic homozygous variant c.C1297T (p.Pro433Ser) in the exon 8 of DONSON gene. This report further expands the genotypic-phenotypic spectrum of the group of disorders known as Cell Cycle-opathies.

Homozygous PCDH12 variants result in phenotype of cerebellar ataxia, dystonia, retinopathy, and dysmorphism.

We report on a sib pair of Indian origin born of a consanguineous parentage with a novel phenotype of distinct facial dysmorphism, cerebellar ataxia, dystonia, and exudative retinopathy due to homozygous PCDH12 nonsense variations. cDNA studies showed >90% reduction in transcript levels in both patients, indicating nonsense-mediated decay and loss of function as the probable causative molecular mechanism of the phenotype.

Whole exome sequencing identifies a novel 5 Mb deletion at 14q12 region in a patient with global developmental delay, microcephaly and seizures.

Rett syndrome is a neurodevelopmental disorder affecting the nervous, musculoskeletal and gastroenteric systems. Affected individuals show normal neonatal development for 6-18 months followed by sudden growth arrest, psychomotor retardation and a broad spectrum of clinical features. Sequence variants in MECP2 gene have been identified as the major genetic etiology accounting for 90-95% of patients. Apart from MECP2, pathogenic sequence variants and copy number variants of FOXG1 gene lead to congenital type of Rett syndrome which is a more severe form and characterised by absence of early normal development as seen in classical Rett syndrome. In this report we describe a female child with global developmental delay, microcephaly and myoclonic seizures harbouring a 5 Mb deletion in 14q12 locus resulting in deletion of single copy of brain specific genes FOXG1, PRKD1 and NOVA1. Whole exome sequencing ruled out any possible role of other pathogenic single nucleotide variants and/or indels as the etiology for the observed phenotype. However, copy number variation analysis from the whole exome data detected a ~ 5 Mb microdeletion at the long arm of chromosome 14q12 region. The deletion was confirmed through array Comparative Genomic Hybridization and validated by quantitative PCR. Further, parents were analysed for mosaicism through metaphase Fluorescence in-situ Hybridisation. Our report broadens the phenotype of atypical Rett syndrome and reiterates the role of exome sequencing not only in detection of point mutation/small indels but also for detection of large deletions/duplication in coding regions.