From the Hansjörg Wyss Department of Plastic Surgery, New York University Langone Health; Department of Surgery, Division of Plastic Surgery, Yale School of Medicine; and Laboratory of Human Genetics and Genomics, The Rockefeller University.
Plast Reconstr Surg. 2022 May 1;149(5):1157-1165. doi: 10.1097/PRS.0000000000008976. Epub 2022 Mar 14.
Nonsyndromic craniosynostosis is one of the most common anomalies treated by craniofacial surgeons. Despite optimal surgical management, nearly half of affected children have subtle neurocognitive deficits. Whereas timing and type of surgical intervention have been studied, the possibility of genetic influence on neurodevelopment in nonsyndromic craniosynostosis patients remains unexplored.
The authors performed whole-exome sequencing for 404 case-parent trios with sporadic nonsyndromic craniosynostosis. Statistical analyses were performed to assess the burden of de novo mutations in cases compared to both expectation and 1789 healthy control trios. Individuals with and without each mutation class were analyzed, and the presence or absence of various types of neurodevelopmental delay were recorded alongside demographic information.
The authors identified a highly significant burden of damaging de novo mutations in mutation-intolerant [probability of loss of function intolerance (pLI) >0.9] genes in nonsyndromic craniosynostosis probands (p = 5.9 × 10-6). Children with these mutations had a two-fold higher incidence of neurodevelopmental delay (p = 0.001) and a more than 20-fold greater incidence of intellectual disability (p = 7.2 × 10-7), and were 3.6-fold more likely to have delays that persisted past 5 years of age (p = 4.4 × 10-4) in comparison with children with nonsyndromic craniosynostosis without these mutations. Transmitted loss of function mutations in high-pLI genes also conferred a 1.9-fold greater risk of neurodevelopmental delay (p = 4.5 ×10-4).
These findings implicate genetic lesions concurrently impacting neurodevelopment and cranial morphogenesis in the pathoetiology of nonsyndromic craniosynostosis and identify a strong genetic influence on neurodevelopmental outcomes in affected children. These findings may eventually prove useful in determining which children with nonsyndromic craniosynostosis are most likely to benefit from surgical intervention.
CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.
非综合征性颅缝早闭是颅面外科医生治疗的最常见畸形之一。尽管进行了最佳的手术治疗，但近一半的受影响儿童仍存在轻微的神经认知缺陷。虽然已经研究了手术干预的时间和类型，但非综合征性颅缝早闭患者的神经发育是否存在遗传影响仍未得到探索。
作者对 404 个散发型非综合征性颅缝早闭的病例-父母三体型进行了全外显子组测序。进行了统计分析，以评估与预期和 1789 个健康对照三体型相比，病例中新生突变的负担。分析了具有和不具有每种突变类型的个体，并记录了各种类型的神经发育迟缓的存在或缺失情况以及人口统计学信息。
作者发现非综合征性颅缝早闭先证者中突变不耐受[功能丧失概率不耐受（pLI）>0.9]基因的破坏性新生突变负担显著增加（p=5.9×10-6）。具有这些突变的儿童神经发育迟缓的发生率增加了两倍（p=0.001），智力残疾的发生率增加了 20 多倍（p=7.2×10-7），并且与没有这些突变的非综合征性颅缝早闭儿童相比，超过 5 岁时仍存在发育迟缓的可能性增加了 3.6 倍（p=4.4×10-4）。高 pLI 基因中的传递性功能丧失突变也使神经发育迟缓的风险增加了 1.9 倍（p=4.5×10-4）。
这些发现表明，同时影响神经发育和颅骨形态发生的遗传病变与非综合征性颅缝早闭的发病机制有关，并确定了遗传对受影响儿童神经发育结果的强烈影响。这些发现最终可能有助于确定哪些非综合征性颅缝早闭儿童最有可能从手术干预中受益。
临床问题/证据水平：风险，III 级。
