The phenotypic spectrum of terminal 6q deletions based on a large cohort derived from social media and literature: a prominent role for DLL1

Individuals were informed about the Chromosome 6 Project and approached to participate via Facebook (Chromosome 6 Facebook group), Twitter (@C6study) and our website (https://​www.​chromosome6.​org). Patients or their legal representatives could participate by signing up via our secured website. Participants received a personal account for the online Chromosome 6 Questionnaire if there was an isolated chromosome 6 aberration and a microarray report was available. Informed consent was obtained through the questionnaire. The accredited Medical Ethics Review Committee of the University Medical Center Groningen waived full ethical evaluation because, according to Dutch guidelines, no ethical approval is necessary if medical information that was already available is used anonymously and no extra tests have to be performed.

Genotype data was extracted from the microarray reports, which were uploaded as part of the sign-up procedure. These microarray analyses were performed in diagnostic laboratories using different platforms. The UCSC LiftOver Tool was used to convert the microarray results to GRCh37/hg19, and the UCSC genome browser was used to visualise the results (http://​genome.​ucsc.​edu).

Phenotype information on pregnancy and birth, congenital abnormalities, relevant dysmorphic features, development, behaviour and health of the child was collected via the multilingual online Chromosome 6 Questionnaire, which was constructed with the MOLGENIS toolkit [5]. Clinical photographs and additional consent for publication were collected. Data collected from individuals in the parent cohort was submitted to the DECIPHER database (https://​decipher.​sanger.​ac.​uk) IDs 489,709–489,746.

Case reports involving terminal 6q deletions were collected using PubMed and the following search criteria: (deletion or monosomy) and (6q26 or 6q27 or terminal 6q). The references were then checked for additional relevant case reports. Publications reporting detailed clinical information and microarray results or comparably detailed breakpoint analyses were included. Clinical information was extracted from the reports using the items of the Chromosome 6 Questionnaire.

Up to September 2021, the Chromosome 6 Questionnaire was completed and submitted by 129 parents, and this included information on 38 individuals with aberrations in the region of interest for this paper. Of these 38, 35 individuals (27 females and 8 males) had a terminal 6q deletion. Another 3 individuals (2 females and 1 male) had an interstitial deletion within the 6q26q27 region. Our literature cohort comprises 58 terminal 6q deletion cases (34 females and 24 males) and 8 interstitial 6q26q27 cases (2 females and 6 males) derived from 29 published papers [1, 6‐33]. In total, 93 terminal 6q deletion cases and 11 interstitial 6q26q27 cases were collected. Case collection is visualised in Additional file 2: Fig. S1. The median age (years;months) of individuals in the parent cohort was 4;6 (range 0;6–32;9) and 12;0 (range 0;0–57;0) in the literature cohort. Data on foetuses was included both in the parent cohort (1 foetus; 23 weeks gestation) and the literature cohort (7 foetuses; median 24 (range 14–30) weeks gestation). For six out of eight of these cases, it was known that the pregnancy was terminated. For the foetus included in the parent cohort, the parents gave us consent to fill out the Chromosome 6 Questionnaire based on the ultrasound and autopsy results. Since the pregnancy was terminated, not all questions could be completed.

Although we focused on isolated terminal and interstitial deletions in the 6q26q27 region, some small additional rearrangements of other chromosomes were included based on their size and gene content (see Additional file 1: Table S1 for details).

Clinical and behavioural characteristics were described as being present, absent or unknown. They are presented here as present/known, where known indicates knowledge of presence or absence. The developmental delay (intelligence quotient (IQ)) was categorised as normal (> 85), borderline (70–85), mild (50–70), moderate (30–50) or severe (< 30) for individuals above the age of 2 years. This was based on formal IQ tests or, if these were not available, the mean of the developmental quotients for the milestones ‘walking independently’ and ‘using two-word sentences’. The developmental quotients were calculated as the 50^th centile of the population age of achievement for that milestone divided by the age of that achievement by the participant times 100. The 50^th centiles of the population age of achievement for the milestones ‘walking independently’ and ‘using two-word sentences’ are 12 [34] and 21 months [35], respectively. For specific milestones, the age and range of achievement were presented, and we used a Mann–Whitney U-test to calculate whether there was a significant difference in the age of milestone achievement between individuals with smaller (those not including the gene QKI) and larger (those including QKI) terminal deletions.

The clinical characteristics of all terminal deletions were described as one group, but we also describe subgroups made to provide information on differently sized deletions and interstitial deletions separately. The terminal 6q deletion subgroups were based on the number of genes involved with a predicted haploinsufficiency (HI) effect. To determine whether genes had a predicted HI-effect, we used HI- and loss-of-function intolerance (pLI) scores as described previously [4] (https://​www.​deciphergenomics​.​org) [36] (http://​exac.​broadinstitute.​org) [37], see Additional file 2: Table S2. Genes with a HI score < 10% and/or a pLI score ≥ 0.9 were considered HI-genes. The terminal 6q26q27 region contains eight such HI-genes: TBP, PSMB1, DLL1, AFDN, PDE10A, QKI, PRKN and MAP3K4. This allocation resulted in eight terminal 6q deletion subgroups: T-PSMB1 (including PSMB1 and TBP), T-DLL1, T-AFDN, T-PDE10A, T-QKI, T-PRKN, T-MAP3K4 and a residual group (T-R) that includes deletions extending beyond 6q26 and including the HI-gene IGF2R (Fig. 1). Two subgroups of interstitial deletions were described: interstitial deletions of 6q26 (I-6q26) and interstitial deletions of 6q27 (I-6q27) (Fig. 1). The phenotypes of individuals with a terminal 6q deletion due to a ring chromosome were compared to those with a simple terminal deletion. We also investigated how often breakpoints in the fragile site FRAE6 (6q26) were present in terminal 6q deletions in order to explore its involvement in breakpoint occurrence.

Many individuals had a small head size (< p10) (60%) and/or plagiocephaly (47%). Some individuals had a short body stature (< p10) (30%). Dysmorphisms included hypertelorism (51%), dysplastic ears (51%) and dental abnormalities (38%). A cleft lip and/or palate was seen in three individuals with larger deletions, see Fig. 2 and Additional file 3: Table S3. Id171 (T-R) also had a choanal stenosis.

Feeding problems (72%) were common, with oral aversion (61%), chewing difficulties (43%), dysphagia (39%) and gastroesophageal reflux (26%) most often reported. Seven individuals needed a gastrostomy, and all seven had a deletion including PRKN. Bowel problems (43%), often constipation (32%), were also reported, but never for the smallest deletions, subgroup T-DLL1 (smaller than 2.7 Mb). Five out of 24 individuals with a deletion including the gene QKI (larger than 7.1 Mb) had an abnormality of the anus, either anal atresia (n = 3) or an ectopic anus (n = 1).

Recurrent infections (42%) were often reported, including of the upper respiratory tract (13/13). Respiratory problems were reported in 26% of the individuals. Sleep apnoea (n = 3) was only present in deletions including at least QKI. Congenital heart defects (CHDs) (12/42), kidney problems (7/37) and abnormalities of the female genitalia (6/27) were only reported in individuals with a deletion including AFDN (larger than 2.7 Mb).

A sacral dimple was reported in 23/31 individuals with a deletion including AFDN. Spina bifida was seen in 5/21 individuals with a deletion including PRKN (larger than 7.9 Mb). Scoliosis (6/39) and abnormal vertebrae (8/38, including hemivertebrae in n = 4) were seen throughout the whole group. Joint hypermobility was present in 64% of all individuals, and hip dysplasia was reported in 6/15 individuals with a PDE10A deletion. In individuals with a deletion including AFDN, a positional foot deformity (8/14) and pes planus (5/14) were reported.

Almost all individuals had brain abnormalities on MRI or CT (91%). Those most often reported were ventriculomegaly/hydrocephaly (51/72), corpus callosum abnormalities (31/72), abnormalities of the cerebellum (18/72) and cortical dysplasia (15/72). In literature, other brain abnormalities were reported that were not included in the Chromosome 6 Questionnaire, these included colpocephaly (n = 8), periventricular nodular heterotopia (PNH) (n = 6), hypoplasia of the hippocampi (n = 5) and a large cisterna magna (n = 5), and all were seen throughout all subgroups [7, 9, 20, 26, 28]. Seizures (67%) (generalised (16/44) and focal onset (20/44)) were often reported, and epilepsy was formally diagnosed in 83% of individuals with seizures. Hypotonia (83%) was very common. Hypertonia was reported in 7/29 individuals, and most of these individuals had a deletion including at least PRKN. 3/17 individuals with a PRKN deletion were reported with spasticity. Balance problems (71%) were often seen. Torticollis (26%), ataxia (38%) and spinal cord abnormalities (39%) were reported throughout the whole group, as well as abnormal pain sensation (30%) and sensory integration disorder (30%).

Almost all individuals had developmental delay (92%), see Table 3 and Additional file 2: Fig. S2. Five individuals had no developmental delay, and their ages ranged from 5 to 49 years and their deletion sizes from 2 to 5.5 Mb, see Additional file 2: Fig. S2 [16, 20]. The level of developmental delay varied considerably within all the subgroups, but was mostly mild to moderate. Individuals without a deletion of QKI (deletion smaller than 7.1 Mb) had normal development to moderate delay, and individuals with a deletion including QKI (larger than 7.1 Mb) had borderline to severe developmental delay.

Ages of achievement for certain milestones are summarised in Table 4 and visualised in Fig. 3. All children with a deletion not including QKI (smaller than 7.1 Mb) were able to perform the milestone ‘walking independently’ at age 3 years and the milestone ‘using two-word sentences’ at age 4 years. For individuals with larger deletions including QKI (larger than 7.1 Mb), some needed more time to achieve these milestones and one individual (Id059) was not yet able to walk independently at age 12 years. The milestones ‘roll over’, ‘sit up unaided’ and ‘pull up in a standing position’ were achieved significantly earlier by children with deletions that did not include QKI. Five out of 22 children reached the milestone ‘fully toilet trained during the day’ at age 4 years.

Two out of seven index patients with an inherited deletion (subgroups T-DLL1 and T-AFDN), inherited this from an independently functioning parent (1 maternal, 1 paternal) [20].

Nineteen out of 93 individuals had reached adulthood, and their median age was 32 years (range 18–57). Detailed information on adult functioning could only be collected for two adults from the parent cohort. One individual needed help with all tasks and was not able to take care of herself (Id059, T-PRKN). The other adult (Id012, T-PRKN) was able to perform simple tasks (for example handling a phone and performing some daily housework) but needed assistance with most tasks.

Some clinical characteristics were reported in literature that were not part of the Chromosome 6 Questionnaire. In addition to the brain abnormalities reported above, micrognathia and high arched palate were reported in 13 and 14 individuals in literature, respectively [1, 7‐10, 13, 19, 23, 26, 28]. These characteristics could also not be related to deletion size.

All five interstitial 6q27 deletion individuals were derived from literature, and the only deleted HI-gene they had in common was DLL1 (Fig. 1). Their phenotype was mostly characterised by brain abnormalities (ventriculomegaly/hydrocephaly, corpus callosum abnormality and cortical dysplasia), epilepsy and mild developmental delay. Other characteristics reported were small head size, strabismus, horseshoe kidney, joint hypermobility, hypotonia, ataxia and autistic behaviour.

There were three interstitial 6q26 deletion individuals in the parent cohort and another three in the literature cohort. PRKN was involved in all deletions, and the largest deletion also encompassed QKI and PDE10A (Fig. 1). Individuals with 6q26 interstitial deletions were mostly characterised by a normal head size and normal body stature, brain abnormalities (delayed myelination, ventriculomegaly/hydrocephaly), vision problems, feeding problems, an abnormal curvature of the spine (scoliosis/kyphosis), hypotonia and insomnia. Other characteristics reported were atrial septal defect (ASD), hydronephrosis, constipation, spina bifida, epilepsy and sleep apnoea. Their behaviour was mostly characterised by social behaviour, hyperactivity, attention deficit disorder and autistic behaviour/disorder. One individual presented self-harming behaviour. Three individuals had no developmental delay, one had borderline delay and one had mild delay (Additional file 2: Fig. S2 and Table 3).

For two individuals, their terminal deletion was known to be the result of a ring chromosome 6 [23, 32]. The ring also included a small terminal 6p deletion without phenotypic consequences [38]. There were no differences in the phenotype between the individuals with a ring chromosome and individuals with a comparable simple deletion.

None of the 93 terminal deletions had a start breakpoint within the fragile site FRA6E (Fig. 1).

The third distally located HI-gene of interest for the common 6q terminal deletion phenotype is DLL1. Recently, Fischer-Zirnsak et al. [29] described 14 patients with pathogenic heterozygous variants of DLL1 and one patient with a deletion including DLL1. These patients presented with hypotonia, scoliosis and a neurodevelopmental phenotype including variable brain abnormalities (ventriculomegaly/hydrocephaly, corpus callosum abnormality and cortical dysplasia), seizures and autism spectrum disorder. This phenotype was registered in OMIM as neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures (NEDBAS, OMIM#618709). Additionally, the following clinical characteristics were reported in at least one patient with a heterozygous DLL1 variant: PNH, large cisterna magna, strabismus, feeding problems, sleep apnoea, recurrent infections, hemivertebrae, sacral dimple, joint hypermobility, ataxia and hyperactivity [29]. As all these clinical characteristics are also seen in our terminal 6q deletion cohorts, it is very likely that haploinsufficiency of DLL1 makes an important contribution to the common terminal 6q deletion phenotype. Lesieur-Sebellin et al. characterised the features detected by prenatal ultrasound in 22 foetuses with terminal 6q deletions and pointed out the gene DLL1 as the major contributor to the detected phenotype [43].

In 2005, Eash et al. [1] reported a patient (Eash_1) with the smallest terminal deletion seen thus far, 390 kb, which only included the HI-genes TBP and PSMB1. This patient’s phenotype was comparable to the common terminal 6q deletion phenotype we describe and included microcephaly, brain abnormalities (corpus callosum abnormality, hydrocephaly), seizures, vertebral abnormalities, hypotonia and developmental delay (Tables 2, 3 and Additional file 3: Table S3; subgroup T-PSMB1). Most other characteristics of the common terminal 6q deletion phenotype were not reported as being present or absent in the Eash et al. case. The breakpoints of this deletion where defined by BAC and PAC FISH clones at approximately 500 kb intervals [1]. If the possible maximum size of the deletion is taken into consideration (Fig. 1), the DLL1 gene could actually be part of the deletion. We tried contacting the authors about additional genetic studies performed for this individual, but without success. Considering the overlapping phenotype and the ambiguities in breakpoint definition, we expect that DLL1 is also part of, or influenced by, the deletion in this case.

DLL1 codes for a ligand of the Notch receptor. The Notch signalling developmental pathway is involved in cell-to-cell communication and cell patterning and differentiation. Notch signalling plays a role in the development of multiple organs and tissues, including the somite-derived organs, nervous system, heart, vasculature, haematopoietic system, cochlea and pancreas [44]. In our cohorts, we did not clearly see any abnormalities for the four latter organ systems, but the nervous system, somite-derived organs and heart were affected.

In mice, delayed expression of Dll1 leads to premature cell differentiation, resulting in a smaller brain and fused vertebrae and ribs [45]. This is in line with the variable brain abnormalities, microcephaly and abnormalities of the vertebrae seen in our cohorts and in the heterozygous DLL1 variant patients reported by Fischer-Zirnsak et al. [29].

CHDs were not reported in the patients by Fischer-Zirnsak et al. [29] and also not seen in our T-DLL1 subgroup, so the effect on heart development may not be fully penetrant. We did find CHDs in larger deletions that include DLL1. In these patients, DLL1 seems the most likely candidate gene to cause CHDs given its role in the Notch pathway and reported pathogenic variants in NOTCH1 in patients with a CHD [46]. During heart development, Notch signalling plays a crucial role in the formation of the membranous walls of the atrial and ventricular chambers and of the outflow tract [47]. Interruption in Notch signalling could explain the CHDs in our cohorts: ASDs, VSDs and a coarctation of the aorta in one individual. Bu et al. reported a patient with an ASD and persistent left superior vena cava with a heterozygous DLL1 variant that was classified as likely pathogenic. This DLL1 variant patient also had a cleft palate, but no further phenotype information was given [48]. A cleft palate was also seen in two of our patients, although these two had the largest terminal deletions of our cohort.

Besides DLL1, other genes were also previously proposed to play a role in the terminal 6q deletion phenotype, especially in larger terminal deletions that display additional clinical characteristics. Below, we briefly summarise these in the context of our findings.Several genes have been linked to brain abnormalities. ERMARD (Endoplasmic Reticulum Membrane-Associated RNA Degradation Protein, MIM*615,532 (also known as C6orf70)) might be involved in PNH, since Conti et al. described nine patients with a deletion including ERMARD and one patient with a heterozygous missense variant and PNH [7]. Unfortunately, we do not have information on the prevalence of PNH for our parent cohort. One patient in our literature cohort did present with PNH, but her deletion did not include ERMARD [28]. ERMARD is also not a predicted HI-gene (%HI: 84.86, pLI: 0.00). Based on this information and the fact that the deletion patients presenting with PNH of Conti et al. all had a deletion that also included DLL1, it remains unclear whether haploinsufficiency of DLL1 or ERMARD, or both, can cause PNH.

Peddibhotla et al. suggested two other genes that may be involved in structural brain abnormalities: THBS2 (Thrombospondin II, MIM*188,061) and PHF10 (Phd Finger Protein 10, MIM*613,069). These genes were deleted in all seven of their terminal 6q deletion patients [9]. However, both genes are not predicted HI-genes, and no pathogenic variants causing structural brain abnormalities in humans have been described thus far.

Lastly, QKI has been linked to brain abnormalities because it plays a role in myelination by regulating several myelin-specific genes [49]. Five individuals in our terminal 6q deletion cohort presented with delayed myelination, and all have a QKI deletion (Additional file 2: Fig. S3). One individual with an interstitial 6q26 deletion (Id073) also presents with delayed myelination, but QKI is not part of her deletion, and 32 out of 37 patients with a deletion of QKI did not have delayed myelination. Likewise, Backx et al. reported a woman with a reciprocal balanced translocation t(5;6)(q23.1;q26) disrupting the QKI gene, resulting in 50% reduced QKI expression, who did not present with myelination problems [50]. Thus, although it is likely that QKI plays a role in myelination, there seems to be incomplete penetrance of this clinical feature.

Vertebral abnormalities are part of the common terminal 6q deletion phenotype, and TBXT (T-Box Transcription Factor T, MIM*601,397) is suggested to play a role in the aetiology of hemivertebrae [18]. An identical missense variant in this gene was identified in three unrelated patients with congenital vertebral malformations. This variant was proposed to increase the risk of congenital vertebral malformations, but not sufficiently on its own [18, 51]. Nevertheless, TBXT was not deleted in all patients with hemivertebrae in our cohort. We therefore think this phenotype is more likely linked to DLL1.

Dental problems, including abnormal morphology and reduced number of teeth, are also part of the common terminal 6q deletion phenotype. The gene SMOC2 is related to dental problems in carriers of pathogenic homozygous variants, including oligodontia, microdontia and abnormally shaped teeth [52‐54]. However, no pathogenic heterozygous SMOC2 variants have been identified thus far, and SMOC2 was not deleted in all individuals with dental problems in our cohort (Additional File 2: Fig. S4).

CHDs were seen in 12 patients with terminal deletions including at least AFDN (deletions larger than 2.7 Mb). Next to DLL1, these deletions also included the gene THBS2. In two large CHD cohort studies, two variants of unknown significance in THBS2 were found. One patient presented with a tetralogy of Fallot [55]. The other patient presented with subaortic stenosis, bicuspid aortic valve, mitral valve stenosis and regurgitation and a coarctation of the aorta [56]. In contrast, our CHD patients mainly presented with septal defects. Since there is no further proof for the role of THBS2 in CHD, and all terminal 6q deletions also include the more likely candidate gene DLL1, we regard the contribution of THBS2 to CHD in the 6q deletion phenotype as less likely.

Recent work showed that QKI also plays a role in cardiovascular development and function in mice and might be involved in cardiomyopathies and cardiovascular disease in humans [57]. One (1/42) of our patients (Id185, aged 1.5 years) with a deletion including QKI was reported to have hypertrophic cardiomyopathy. Further research is needed to investigate whether there is a relation between cardiomyopathies and a deletion of QKI and thus whether individuals with a QKI deletion need to be screened for cardiomyopathy.

Almost all the individuals in our cohort with a deletion including DLL1 had developmental delay. Besides DLL1, QKI seems to mark a tipping point in the extent of developmental delay. Normal development was seen in a couple of individuals without a deletion of QKI, whereas severe developmental delay was only seen in individuals with a deletion including QKI (Additional file 2: Fig. S2, Table 3). The woman with a reciprocal balanced translocation t(5;6)(q23.1;q26) disrupting the QKI gene reported by Backx et al. also presented with borderline developmental delay [50]. QKI probably has an additive effect on the level of developmental delay next to the deletion of DLL1, which on its own can lead to moderate developmental delay in small (500 kb) deletions [28].

A range of behavioural problems was seen throughout the whole group of terminal deletions, with information available for all 34 individuals from the parent cohort but only 8 of 51 literature cases, foetuses excluded (Additional file 3: Table S3). Self-harming behaviour was seen significantly (Fisher’s Exact Test p = 0.03) more often in the larger terminal deletions. Fischer et al. reported autism spectrum disorder as part of the syndrome linked to DLL1 haploinsufficiency. In their cohort, 5 out of their 13 DLL1 variant patients and their one DLL1 deletion patient had autism spectrum disorder [29]. In our cohorts, however, autistic behaviour was present in only 4/33 individuals with a terminal deletion including DLL1. However, autistic behaviour was also seen in 3/5 individuals with an interstitial 6q26 deletion that did not include DLL1, suggesting that DLL1 haploinsufficiency is not the only cause for autistic behaviour.

The individuals with terminal 6q deletions included in our cohort were grouped based on the number of predicted HI-genes involved in their deletion. However, only two HI-genes, DLL1 and QKI, could be linked to some of the observed clinical characteristics. This is reflected in the phenotypic differences between the patients with deletions smaller and larger than 7.1 Mb.

It has been suggested that the FRA6E fragile site is the cause of the breakpoints in terminal 6q deletions [3, 12, 13]. FRA6E is a common fragile site located at 161.71–161.91 Mb in 6q26 (Fig. 1). Common fragile sites are associated with hotspots for chromosome aberration breakpoints [58] due to an impaired replication process at the fragile site. Nevertheless, Palumbo et al. showed that the replication process at FRA6E is not impaired [59], and we also do not see a clustering of breakpoints within or near the fragile site in our data.

The common terminal 6q deletion phenotype is highly variable, and not all clinical characteristics are present in each individual. Therefore clinical follow-up and surveillance should be focused on the congenital anomalies present and the problems experienced. This also means that the phenotype should be fully assessed upon diagnosis to establish which of the comorbidities known for this chromosomal aberration are present in the patient. In Table 5, we present our recommendations for investigations for terminal 6q deletions < 7.1 Mb and for deletions > 7.1 Mb including the gene QKI. We recommend that all individuals should be offered a neurological investigation (including an MRI upon indication), a cardiac ultrasound (at least once), an investigation by an ophthalmologist and an annual vision assessment at younger ages and upon indication at older ages. As seizures are seen in a large proportion of the individuals, the threshold should be low for consulting a (paediatric) neurologist and for performing an EEG. Individuals with hypermobility can benefit from physiotherapy and medical aids. For individuals with deletions > 7.1 Mb, clinicians should also be aware of the occurrence of cleft palate, anal atresia and sleep apnoea, which are reported in some individuals and can be treated. Some individuals with deletions > 7.1 Mb have spina bifida, although vertebral abnormalities that could cause scoliosis are seen for all deletion sizes. Performing an X-ray of the vertebral column can help identify these abnormalities. Besides this specific advice for individuals with a terminal 6q deletion, appropriate support for feeding, behavioural and sleeping problems should also be in place.

Development was delayed in most individuals, and those with deletions > 7.1 Mb needed more time to achieve developmental milestones than those with deletions < 7.1 Mb. Nonetheless, all but one individual did achieve the milestones ‘walking independently’ and ‘using two-word sentences’ (Table 4 and Fig. 3). As in all neurodevelopmental disorders, the definite aim should be to optimise the developmental abilities and quality of life of the individual with a chromosomal aberration and their family. Having more detailed information available on what to expect is an important step in this process.

Recruiting parents via social media and collecting phenotypes directly from the parents via the online Chromosome 6 Questionnaire resulted in an extensive dataset for the parent cohort. However, not all clinical characteristics were addressed in literature, resulting in missing data. For example, it was only known for one out of ten (10%) individuals in the T-PDE10A subgroup if they had sleeping problems, while this was known for 14 out of 20 (70%) in the T-PRKN subgroup. The main difference between these subgroups was the ratio of parent cohort versus literature cohort cases, which was 1:9 for T-PDE10a and 15:5 for T-PRKN. In another study, we investigated the availability of data on specific phenotype information in literature case reports compared to data collected directly from parents in the terminal 6q deletion cohort presented here. We show that we collected significantly more data from parents, for almost all phenotypic features, in comparison to the literature [60].

Our phenotype data was collected directly from parents, which might raise questions on the quality of the data. However, in our data consistency study we show that phenotype data collected directly from parents is highly consistent with data extracted from the medical files on the same individual [60].