Benefits of clinical criteria and high-throughput sequencing for diagnosing children with syndromic craniosynostosis

Abstract

An accurate diagnosis of syndromic craniosynostosis (CS) is important for personalized treatment, surveillance, and genetic counselling. We describe detailed clinical criteria for syndromic CS and the distribution of genetic diagnoses within the cohort. The prospective registry of the Norwegian National Unit for Craniofacial Surgery was used to retrieve individuals with syndromic CS born between 1 January 2002 and 30 June 2019. All individuals were assessed by a clinical geneticist and classified using defined clinical criteria. A stepwise approach consisting of single-gene analysis, comparative genomic hybridization (aCGH), and exome-based high-throughput sequencing, first filtering for 72 genes associated with syndromic CS, followed by an extended trio-based panel of 1570 genes were offered to all syndromic CS cases. A total of 381 individuals were registered with CS, of whom 104 (27%) were clinically classified as syndromic CS. Using the single-gene analysis, aCGH, and custom-designed panel, a genetic diagnosis was confirmed in 73% of the individuals (n = 94). The diagnostic yield increased to 84% after adding the results from the extended trio-based panel. Common causes of syndromic CS were found in 53 individuals (56%), whereas 26 (28%) had other genetic syndromes, including 17 individuals with syndromes not commonly associated with CS. Only 15 individuals (16%) had negative genetic analyses. Using the defined combination of clinical criteria, we detected among the highest numbers of syndromic CS cases reported, confirmed by a high genetic diagnostic yield of 84%. The observed genetic heterogeneity encourages a broad genetic approach in diagnosing syndromic CS.

Evaluating the performance of a clinical genome sequencing program for diagnosis of rare genetic disease, seen through the lens of craniosynostosis

“…In the Oxford survey [17], pathogenic variants in 20 rarely involved genes accounted for 23/666 (3.5%) of all cases, and in the exome/genome sequencing study [20], the 15 new diagnoses were identified in 14 different genes. A recent study from Norway reported similar findings [21]. As we expect the patients enrolled into 100kGP to be enriched for rare genetic causes, this heterogeneity presents a substantial challenge for pipeline-based diagnosis, so we considered that CRS could represent a stringent test of how well the GE/GMC pipeline worked.…”

“…Our analysis of CRS may not be representative of 100kGP data overall. Craniosynostosis likely represents a stringent test of the GS pipeline, given the extensive prior molecular and phenotypic screening undertaken before case recruitment (Box S1), and because CRS is known to be associated with a long tail of rare genetic diagnoses [17,21]. The reliance of GE/GMC on a panelbased diagnostic approach was evidently not well suited to this scenario.…”

“…A recent study from Norway reported similar findings. 21 As we expect the patients enrolled into 100kGP to be enriched for rare genetic causes, this heterogeneity presents a substantial challenge for pipeline-based diagnosis, so we considered that CRS could represent a stringent test of how well the GE/GMC pipeline worked. This work demonstrates the substantial benefit of exploiting specialist research expertise to augment the overall diagnostic rate in 100kGP, and indicates ways in which the diagnostic pipeline could be improved.…”

Missense and truncating variants in CHD5 in a dominant neurodevelopmental disorder with intellectual disability, behavioral disturbances, and epilepsy

“…Notably, seizures are rarely observed in patients with CHD4 variants and occur only in a minority of patient with CHD3 alterations. Also craniosynostosis has been rarely reported in association with variants in other CHD genes (Siakallis et al 2019 ; Tønne et al 2020 ). In our cohort, craniosynostosis was observed in two individuals belonging to different families and in one patient with a de novo variant.…”

Dissection of contiguous gene effects for deletions around ERF on chromosome 19

“…Disease‐causing heterozygous loss‐of‐function variants of ERF were first described in 2013, in 12 families segregating features of a newly recognized syndrome (termed ERF ‐related craniosynostosis or craniosynostosis type 4, OMIM# 600775), characterized by premature fusion of the cranial sutures (craniosynostosis), hypertelorism, and mild midface hypoplasia (Twigg et al, 2013). Confirmatory case reports have followed (Chaudhry et al, 2015; Korberg et al, 2020; Lee et al, 2018; Provenzano et al, 2021; Timberlake et al, 2017; Tønne et al, 2020; Yoon et al, 2020), and the clinical features of the disorder were further delineated and summarized in 16 additional families by Glass et al (2019). In addition to craniosynostosis and facial dysmorphism, additional frequently associated features included Chiari‐1 malformation, speech and language delay, poor gross and/or fine motor control, hyperactivity, and poor concentration.…”