Duplication at 19q13.32q13.33 Segregating with Neuropsychiatric Phenotype in a Three-Generation Family: Towards the Definition of a Critical Region.

Chromosomal submicroscopic imbalances represent well-known causes of neurodevelopmental disorders. In some cases, these can cause specific autosomal dominant syndromes, with high-to-complete penetrance and de novo occurrence of the variant. In other cases, they result in non-syndromic neurodevelopmental disorders, often acting as moderate-penetrance risk factors, possibly inherited from unaffected parents. We describe a three-generation family with non-syndromic neuropsychiatric features segregating with a novel 19q13.32q13.33 microduplication. The propositus was a 28-month-old male ascertained for psychomotor delay, with no dysmorphic features or malformations. His mother had Attention-Deficit/Hyperactivity Disorder and a learning disability. The maternal uncle had an intellectual disability. Chromosomal microarray analysis identified a 969 kb 19q13.32q13.33 microduplication in the proband. The variant segregated in the mother, the uncle, and the maternal grandmother of the proband, who also presented neuropsychiatric disorders. Fragile-X Syndrome testing was negative. Exome Sequencing did not identify Pathogenic/Likely Pathogenic variants. Imbalances involving 19q13.32 and 19q13.33 are associated with neurodevelopmental delay. A review of the reported microduplications allowed to propose BICRA (MIM *605690) and KPTN (MIM *615620) as candidates for the neurodevelopmental delay susceptibility in 19q13.32q13.33 copy number gains. The peculiarities of this case are the small extension of the duplication, the three-generation segregation, and the full penetrance of the phenotype.

Prenatal Exome Sequencing: Background, Current Practice and Future Perspectives-A Systematic Review.

The introduction of Next Generation Sequencing (NGS) technologies has exerted a significant impact on prenatal diagnosis. Prenatal Exome Sequencing (pES) is performed with increasing frequency in fetuses with structural anomalies and negative chromosomal analysis. The actual diagnostic value varies extensively, and the role of incidental/secondary or inconclusive findings and negative results has not been fully ascertained. We performed a systematic literature review to evaluate the diagnostic yield, as well as inconclusive and negative-result rates of pES. Papers were divided in two groups. The former includes fetuses presenting structural anomalies, regardless the involved organ; the latter focuses on specific class anomalies. Available findings on non-informative or negative results were gathered as well. In the first group, the weighted average diagnostic yield resulted 19%, and inconclusive finding rate 12%. In the second group, the percentages were extremely variable due to differences in sample sizes and inclusion criteria, which constitute major determinants of pES efficiency. Diagnostic pES availability and its application have a pivotal role in prenatal diagnosis, though more homogeneity in access criteria and a consensus on clinical management of controversial information management is envisageable to reach widespread use in the near future.

The ontogeny of fidgety movements from 4 to 20weeks post-term age in healthy full-term infants.

BACKGROUND: Fidgety movements (FMs) are an early accurate marker for normal development. AIM: The study assessed the ontogeny of normal FMs from 4 to 20weeks post-term age (PTA). STUDY DESIGN: Longitudinal prospective study of healthy full-term infants video recorded every second week from birth to 20weeks PTA. SUBJECTS: 21 full-term newborns were enrolled. OUTCOME MEASURES: Temporal organization, amplitude, character, predominance in proximal and/or distal parts of the body and the presence of FMs in fingers and wrists were independently scored by three observers. RESULTS: From 4 to 10weeks PTA, FMs were sporadic, becoming intermittent in 1-2weeks; they occurred in the proximal parts, with larger and jerkier movements in the following period. From 11 to 16weeks PTA FMs became smaller in amplitude and slower in speed, they were present in all body parts and were more continual than before. Rotational movements in wrists and ankles and finger movements with open hands appeared. From 17 to 20weeks PTA, FMs became more discontinuous and disappeared at 18-20weeks PTA. CONCLUSIONS: Developmental course of FMs was seen between 4 and 20weeks PTA with changes in temporal organization, amplitude, speed and body parts involved. The best time for scoring FMs is between 12 and 16weeks PTA.