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We have recently collected clinical information on 37 individuals with deletion of 22q13 and compared the features of these individuals with 24 previously reported cases. The features most frequently associated with this deletion are global developmental delay, generalized hypotonia, absent or severely delayed speech, and normal to advanced growth. Minor anomalies include dolicocephaly, abnormal ears, ptosis, dysplastic toenails, and relatively large hands. As with many terminal deletions involving pale G-band regions, the deletion can be extremely subtle and can go undetected on routine cytogenetic analysis. In fact, 32% of the individuals in our study had previous chromosome analyses that failed to detect the deletion. Eight of 37 individuals had deletion of 22q13 secondary to an unbalanced chromosome translocation. In the newborn, this deletion should be considered in cases of hypotonia for which other common causes have been excluded. In the older child, this syndrome should be suspected in individuals with normal growth, profound developmental delay, absent or delayed speech, and minor dysmorphic features. We recommend high-resolution chromosome analysis and fluorescence in situ hybridization studies, or molecular analysis to exclude this diagnosis.

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The deletion 22q13 syndrome results from loss of a segment of the distal long arm of chromosome 22. Simple deletions, rings, unbalanced translocations, and other less common structural chromosome abnormalities have been associated with this deletion syndrome. The major clinical features are neonatal hypotonia, global developmental delay, absent or severely delayed speech, and normal to accelerated growth. Facial features include dolichocephaly, full brow, flat midface, wide nasal bridge, bulbous nose, deep‐set eyes, ptosis, long eyelashes, puffy eyelids, full cheeks, and prominent ears. Other common features are large fleshy hands, dysplastic toenails, high tolerance to pain, and mouthing or chewing behaviors. Less common features are arachnoid cysts, lymphedema, and hearing loss. There are no apparent life‐threatening defects of the organ systems. Therapies to improve muscle tone, coordination, strength, cognitive skills, and communication skills are beneficial to many individuals. Haploinsufficiency for the gene SHANK3/PROSAP2 is the most likely cause for the neurological deficits associated with deletion 22q13. The eponym for deletion 22q13 is Phelan‐McDermid Syndrome

Mutations in nuclear genes required for the replication and maintenance of mitochondrial DNA cause progressive multisystemic neuromuscular disorders with overlapping phenotypes. Biallelic mutations in C10orf2, encoding the Twinkle mitochondrial DNA helicase, lead to infantile-onset cerebellar ataxia (IOSCA), as well as milder and more severe phenotypes. We present a 13-year-old girl with ataxia, severe hearing loss, optic atrophy, peripheral neuropathy, and hypergonadotropic hypogonadism. Whole-exome sequencing revealed that the patient is compound heterozygous for previously unreported variants in the C10orf2 gene: a paternally inherited frameshift variant (c.333delT; p.L112Sfs*3) and a maternally inherited missense variant (c.904C>T; p.R302W). The identification of novel C10orf2 mutations extends the spectrum of mutations in the Twinkle helicase causing recessive disease, in particular the intermediate IOSCA phenotype. Structural modeling suggests that the p.R302W mutation and many other recessively inherited Twinkle mutations impact the position or interactions of the linker region, which is critical for the oligomeric ring structure and activity of the helicase. This study emphasizes the utility of whole-exome sequencing for the genetic diagnosis of a complex multisystemic disorder.