Exome Sequencing Reveals Novel Variants and Expands the Genetic Landscape for Congenital Microcephaly.

Congenital microcephaly causes smaller than average head circumference relative to age, sex and ethnicity and is most usually associated with a variety of neurodevelopmental disorders. The underlying etiology is highly heterogeneous and can be either environmental or genetic. Disruption of any one of multiple biological processes, such as those underlying neurogenesis, cell cycle and division, DNA repair or transcription regulation, can result in microcephaly. This etiological heterogeneity manifests in a clinical variability and presents a major diagnostic and therapeutic challenge, leaving an unacceptably large proportion of over half of microcephaly patients without molecular diagnosis. To elucidate the clinical and genetic landscapes of congenital microcephaly, we sequenced the exomes of 191 clinically diagnosed patients with microcephaly as one of the features. We established a molecular basis for microcephaly in 71 patients (37%), and detected novel variants in five high confidence candidate genes previously unassociated with this condition. We report a large number of patients with mutations in tubulin-related genes in our cohort as well as higher incidence of pathogenic mutations in MCPH genes. Our study expands the phenotypic and genetic landscape of microcephaly, facilitating differential clinical diagnoses for disorders associated with most commonly disrupted genes in our cohort.

Trisomy 22pter-q12.3 presenting with hepatic dysfunction variability of cat-eye syndrome.

We describe the clinical characteristics of two patients with cat-eye syndrome (CES, MIM #115470) resulting from a supernumerary marker chromosome that includes 22pter-q12.3. They both presented a constellation of features typical of CES, including coloboma, auricular malformations, heart and renal anomalies, as well as hepatic dysfunction, which led to severe effects. In one case Pierre Robin sequence was diagnosed which has not been described earlier in this trisomy. Although CES is a well known, but infrequently diagnosed disorder, we draw attention both to its clinical overlaps with other disorders and, in view of the clinical variability being identified within the 22q11 region, to the importance of careful molecular examination of proximal 22q in patients with suggestive clinical signs.