Targeted next-generation sequencing in the diagnosis of neurodevelopmental disorders.

We developed a next-generation sequencing (NGS) based mutation screening strategy for neurodevelopmental diseases. Using this system, we screened 284 genes in 40 patients. Several novel mutations were discovered. Patient 1 had a novel mutation in ACTB. Her dysmorphic feature was mild for Baraitser-Winter syndrome. Patient 2 had a truncating mutation of DYRK1A. She lacked microcephaly, which was previously assumed to be a constant feature of DYRK1A loss of function. Patient 3 had a novel mutation in GABRD gene. She showed Rett syndrome like features. Patient 4 was diagnosed with Noonan syndrome with PTPN11 mutation. He showed complete agenesis of corpus callosum. We have discussed these novel findings.

Cri-du-Chat Syndrome Cytogenetically Cryptic Recombination Aneusomy of Chromosome 5: Implications in Recurrence Risk Estimation.

Cri-du-chat syndrome is caused by haploinsufficiency of the genes on the distal part of the short arm of chromosome 5, and characteristic features include microcephaly, developmental delays, and a distinctive high-pitched mewing cry. Most cri-du-chat syndrome cases result from a sporadic de novo deletion that is associated with a low recurrence risk. On rare occasions, however, cri-du-chat syndrome with 5p monosomy can be accompanied by 5q trisomy. This combination is virtually always associated with parental large pericentric inversions. Among previously reported cri-du-chat syndrome cases with 5p monosomy accompanied by 5q trisomy, the aneusomy of chromosome 5 in all but one case was cytogenetically visible using G-banding. When an accompanying 5q trisomy is detected, a significant recurrence risk is expected. We here report on a patient with cri-du-chat syndrome phenotype who initially exhibited a normal karyotype on G-banding but in whom molecular analysis using multiplex ligation-dependent probe amplification and array comparative genomic hybridization revealed a 5p deletion accompanied by a 5q duplication. Parental chromosomal testing led to the identification of a very large pericentric inversion, of which breakpoints resided at the terminal regions of 5p15.31 and 5q35.1. This information was vital for counseling the family regarding the significantly high recurrence risk.

Juvenile Muscular Atrophy of a Unilateral Upper Extremity (Hirayama Disease) in a Patient with CHARGE Syndrome.

CHARGE syndrome is an autosomal dominant congenital anomaly syndrome, and the causative gene is CHD7. We report a patient with a CHD7 mutation who presented with juvenile muscular atrophy of a unilateral upper extremity, a presumably heterogeneous condition that is also known as Hirayama disease. This association has not been previously described. Weakness and atrophy of the hands should be carefully examined in patients with CHARGE syndrome, since Hirayama disease might be a possible complication in adolescent patients with this syndrome.

Diversity of supernumerary tooth formation in siblings with cleidocranial dysplasia having identical mutation in RUNX2 : possible involvement of non-genetic or epigenetic regulation.

INTRODUCTION: Cleidocranial dysplasia (CCD, MIM #119600) is an autosomal-dominant disorder characterized by hypoplasia or aplasia of clavicles, patent fontanelles and short stature. The responsible gene has been identified as RUNX2. CCD is also accompanied by characteristic dental abnormalities, e.g. supernumerary teeth, delayed eruption and impaction of permanent teeth. Intrafamilial variations of skeletal abnormalities are reported but those of dental abnormalities are obscure. To clarify this point, a precise examination of the dental features of CCD siblings having identical mutation was performed. DESIGN: Gene mutational analysis of three Japanese CCD siblings and their father was performed. Skeletal and dental characteristics were examined by the inquiry and radiographs. RESULTS: Three siblings uniformly showed patent fontanelles and short stature. They and their father had a novel missense mutation in the RUNT-domain (P210S) of RUNX2. The siblings were completely discordant for the dental characteristics with the position and number of supernumerary teeth being completely different. The youngest, a 12-year-old boy, had six supernumerary teeth, which appeared symmetrically around the maxillary canines and mandibular premolars. The second, a 15-year-old girl, had four supernumerary teeth which appeared around the mandibular incisors. The oldest, a 17-year-old boy, had 11 supernumerary teeth, which were symmetrically around the mandibular lateral dentition and asymmetrically around the maxillary incisors and premolars. CONCLUSION: The present study suggests the involvement of non-genetic or epigenetic regulation in supernumerary tooth formation in CCD.