Neurodevelopmental disorders (NDDs) are clinically and genetically heterogenous; many such disorders are secondary to perturbation in brain development and/or function. The prevalence of NDDs is > 3%, resulting in significant sociocultural and economic challenges to society. With recent advances in family-based genomics, rare-variant analyses, and further exploration of the Clan Genomics hypothesis, there has been a logarithmic explosion in neurogenetic “disease-associated genes” molecular etiology and biology of NDDs; however, the majority of NDDs remain molecularly undiagnosed. We applied genome-wide screening technologies, including exome sequencing (ES) and whole-genome sequencing (WGS), to identify the molecular etiology of 234 newly enrolled subjects and 20 previously unsolved Turkish NDD families. In 176 of the 234 studied families (75.2%), a plausible and genetically parsimonious molecular etiology was identified. Out of 176 solved families, deleterious variants were identified in 218 distinct genes, further documenting the enormous genetic heterogeneity and diverse perturbations in human biology underlying NDDs. We propose 86 candidate disease-trait-associated genes for an NDD phenotype. Importantly, on the basis of objective and internally established variant prioritization criteria, we identified 51 families (51/176 = 28.9%) with multilocus pathogenic variation (MPV), mostly driven by runs of homozygosity (ROHs) – reflecting genomic segments/haplotypes that are identical-by-descent. Furthermore, with the use of additional bioinformatic tools and expansion of ES to additional family members, we established a molecular diagnosis in 5 out of 20 families (25%) who remained undiagnosed in our previously studied NDD cohort emanating from Turkey.

神经发育障碍（NDD）在临床和遗传上是异质的；许多此类疾病继发于大脑发育和/或功能紊乱。NDD 的流行率 > 3%，给社会带来了重大的社会文化和经济挑战。随着基于家族的基因组学、稀有变异分析的最新进展以及对氏族基因组学假设的进一步探索，神经遗传“疾病相关基因”分子病因学和 NDD 生物学出现了对数爆炸；然而，大多数 NDD 仍未得到分子诊断。我们应用了全基因组筛选技术，包括外显子组测序 (ES) 和全基因组测序 (WGS)，以确定 234 名新登记受试者和 20 个以前未解决的土耳其 NDD 家族的分子病因。在 234 个研究家庭中的 176 个（75. 2%)，确定了一种合理且遗传简约的分子病因。在 176 个已解决的家族中，在 218 个不同的基因中发现了有害变异，进一步证明了 NDD 背后的人类生物学中巨大的遗传异质性和多样的扰动。我们为 NDD 表型提出了 86 个候选疾病特征相关基因。重要的是，根据客观和内部建立的变异优先标准，我们确定了 51 个家族 (51/176 = 28.9%) 具有多位点致病变异 (MPV)，主要由纯合子 (ROH) 驱动 - 反映基因组片段/单倍型血统相同。此外，随着使用额外的生物信息学工具和 ES 扩展到额外的家庭成员，