Clinical and genomic characterization of 8p cytogenomic disorders (2024)

Demographics

We enrolled 97 individuals with documented chromosome 8p rearrangements. The majority of the participants were from the United States (n = 53), the United Kingdom (n = 14), and other European countries (n = 20). We report on 52 individuals with invdupdel(8p), 37 with del(8p), and 8 with dup(8p) (TableS1). Demographic and clinical characteristics of each rearrangement group are summarized in Table1, and detailed data are provided in TableS1.

Molecular findings

Deletion/duplication patterns

We used the UCSC Genome Browser to visualize and compare the breakpoints of each individual within each rearrangement group (Fig.1). We attribute the small variations (~0.1–0.3 Mb) between similar breakpoint patterns to variations in microarray versions and platforms, and difficulty accurately assessing sizes of CNVs associated with LCRs. Larger (~0.5–1.5 Mb) variations of breakpoints for recurrent deletions and/or duplications can be attributable to large LCR regions spanning all breakpoints.

Eighty-one individuals had recurrent rearrangements of invdupdel(8p) (n = 49), del(8p)_distal (n = 4), del(8p)_proximal&distal (n = 9), del(8p)_proximal (n = 12), and dup(8p) (n = 7); the latter including the five individuals from the literature. The detailed description of breakpoint coordinates and visual representation of each recurrent and nonrecurrent (n = 21) rearrangement is given in Supplementary Materials (Table S1 and Figs. S1–3). Briefly, the shared deleted interval in individuals with invdupdel(8p) was the most distal 6.7 Mb and the shared duplicated interval was approximately 11.1 Mb. Individuals with del(8p) were grouped into three subcategories based on the location of their deletions: (1) del(8p)_distal, (2) del(8p)_proximal, (3) del(8p)_proximal&distal (Fig.1). The shared deleted intervals were 6.7 Mb, 3.8 Mb, and 10.7 Mb for del(8p)_distal, del(8p)_proximal, and del(8p)_proximal&distal. The shared duplicated interval was 3.7 Mb in individuals with dup(8p)_proximal.

Gene content and candidate gene prioritization

Chromosome 8p contains ~250 protein-coding genes, and almost every gene is included in at least one of the recurrent rearrangements. The detailed information such as chromosome 8p coordinates, gene constraint metrics, OMIM disease entries, gene functions, and animal models for each gene can be found in TableS2. Briefly, we prioritized the candidate genes DLGAP2 and CSMD1 for del(8p) distal and the deleted segment of invdupdel(8p), GATA4 and XKR6 for del(8p)_proximal and dup(8p)_proximal, and RHOBTB2 and CHRNA2 for the duplicated segment of invdupdel(8p) (Supplemental Data).

Clinical findings of recurrent cohort

Clinical findings of the recurrent cohort are summarized and compared among subgroups in Table1, and the most prominent findings by organ systems are outlined in the following sections. Detailed data on clinical findings of each individual, including the individuals with nonrecurrent 8p rearrangements, are given in TableS1. Since individuals with invdupdel(8p) had similar deletion breakpoints and sizes, and also similar proximal duplication breakpoints, they are grouped altogether given the similarity in clinical findings. However, seizures and corpus callosum abnormalities were separated by the distal breakpoint coordinates, and hence sizes, of their inverted duplications. We only report anthropometric measurements, developmental milestones, and cardiac findings for the dup(8p)_proximal cohort.

Prenatal and neonatal findings

Single umbilical artery, small for gestational age (SGA), and congenital heart defects are the most commonly reported findings in individuals with invdupdel(8p), del(8p)_proximal&distal, and del(8p)_proximal (Table1). Oligohydramnios/polyhydramnios, intracranial cyst, reduced fetal movement, preeclampsia, and gestational diabetes mellitus were less frequently reported (TableS1).

The majority of individuals in each category had at least one neonatal finding with hypotonia being the most commonly reported. Respiratory distress, transient hypoglycemia and thermoregulation issues in term neonates, stiffness, torticollis, nuchal cord, polycythemia, and seizures were among other reported neonatal issues (Table1 and TableS1).

The distributions of birth weight, length, and OFC Z-scores are shown in Figure S4, and the corresponding values in Table1. While most individuals across all rearrangements had Z-scores within 2 SD for all anthropometric measurements, individuals with del(8p)_proximal had lower average Z-scores for birth weight and length than individuals with other rearrangements. Individuals with del(8p)_proximal and del(8p)_proximal&distal had lower average Z-scores for birth OFC than individuals with other rearrangements. Of the individuals who were reported to be SGA prenatally, five of seven with invdupdel(8p), two of three with del(8p)_proximal, and three of three with del(8p)_proximal&distal were also born with birth weight less than the 10th percentile.

Growth and endocrine issues

Short stature was reported in 10–20% of individuals across all rearrangements (Table1). Individuals with short stature generally had other issues such as past and/or current feeding difficulty along with lower concurrent weight Z-scores, history of being SGA, and/or prematurity (TableS1).

No individual with invdupdel(8p) was overweight or obese. However, 30–67% of individuals with del(8p) were overweight (Table1), of whom only two adult individuals with del(8p)_proximal&distal and del(8p)_distal had short stature. Precocious puberty, hypothyroidism/hyperthyroidism, diabetes mellitus, and low cortisol levels were among other occasionally reported endocrine issues (TableS1).

Neurodevelopmental milestones

The box plot distributions of developmental milestones (age at sitting, age at walking, and age at first words) are shown in Fig.2. All individuals across all rearrangements had a delay in at least one developmental milestone with most individuals having global developmental delay. In general, individuals with invdupdel(8p) had more moderate-to-severe delays in all milestones compared to individuals with del(8p).

Of those who have spoken their first words, 4 of 15 individuals with invdupdel(8p) (average age = 48 months), 5 of 8 individuals with del(8p)_proximal (average age = 29.4 months), 5 of 7 individuals with del(8p)_proximal&distal (average age = 53 months), and all 3 individuals with del(8p)_distal (average age = 40.6 months) have also started speaking in short sentences. However, apart from four individuals with del(8p), all individuals have speech difficulties ranging from limited vocabulary to slurred speech, and many of them receive speech therapy. Speech difficulties are more severe in individuals with invdupdel(8p) than individuals with del(8p). The average age of 11 individuals with invdupdel(8p) who have spoken their first words but have yet to speak their first sentences was 70 months.

Although intelligence quotients were not available (many not testable), all individuals were reported to have some degree of intellectual disability and/or developmental delay (ID/DD), with individuals with del(8p) having milder neurocognitive deficits than individuals with invdupdel(8p). One adult with del(8p)_distal is attending university and another one was able to obtain a driver’s license. The major issues in both individuals are mild learning disabilities and neurobehavioral/psychiatric issues such as short attention span, anxiety, and depression.

The average Vineland adaptive behavioral composite (ABC) scores were 52, 66, 45, and 66 for individuals with invdupdel(8p) (n = 39), del(8p)_distal (n = 3), del(8p)_proximal&distal (n = 8), and del(8p)_proximal (n = 7), respectively. Communication was the most severely affected subdomain in individuals with invdupdel(8p), del(8p)_distal, and del(8p)_proximal&distal (Figure S5).

Seizures

Twenty-seven individuals with invdupdel(8p), ten individuals with del(8p) (five with del[8p]_proximal, four with del[8p]_proximal&distal, and one with del[8p]_distal) were reported to have had at least one seizure (Table1 and Table S1).

Seizure characteristics in individuals with del(8p)

Each of the ten individuals across del(8p) subgroups had only one seizure type, and there was no prominent seizure type or recurrent seizure characteristics. In eight individuals, seizures started between 2 and 5 years of ages. Four of five individuals who had relatively more frequent seizures reported seizure control with sodium valproate. Five individuals have been followed without any antiepileptic medication.

Seizure characteristics in individuals with invdupdel(8p)

Absence seizures were the most commonly reported seizure type in individuals with invdupdel(8p) followed by motor and febrile seizures (Table1). Eleven of 27 individuals were reported to have more than one seizure type (TableS1).

The seizures usually started between 1 and 4 years of age (n = 20). The number of lifetime seizures tended to be either 1–10 or >100. Among the latter group, the frequency of seizures ranged between several times a day to 1–3 times a month. Absence seizures usually lasted less than a minute, and only two individuals with motor seizures reported one status epilepticus episode each.

There was no specific EEG abnormality in 36 individuals with invdupdel(8p) who had at least one EEG evaluation, yet half were found to have an abnormal EEG (Table1). Generalized slowing (n = 9, 26%) and epileptiform charges (n = 7, 20%) were the most commonly reported EEG abnormalities (TableS1). Four individuals were found to have nonspecific abnormal EEG without clinical seizures.

While there was no observable relationship between the occurrence, number, or frequency of absence seizures and distal duplication breakpoints, motor seizures were more commonly reported in individuals with more distal duplication breakpoints. While 9 of 25 individuals (36%) with distal duplication breakpoints after base pairs 37,000,000 had motor seizures, only 4 of 25 individuals (17%) with distal duplication breakpoints before base pairs 37,000,000 had motor seizures (TableS1).

Many individuals with invdupdel(8p) had medically manageable seizures. Levetiracetam, sodium valproate, oxcarbazepine, phenobarbital, topiramate, and phenytoin were used as monotherapy or in combinations. Twenty individuals no longer require antiepileptics.

Structural brain abnormalities

Structural brain abnormalities were commonly reported in individuals with invdupdel(8p), with agenesis/hypoplasia of the corpus callosum being the most common finding followed by hydrocephalus/ventriculomegaly and cerebral/cerebellar atrophy (Table1). Most hydrocephalus cases were mild/benign and did not require shunt placement. Individuals with del(8p) occasionally had abnormal brain MRIs, and only one with del(8p)_distal was reported to have hypoplasia of the corpus callosum.

Of the individuals with distal duplication breakpoints before base pairs 37,000,000 (n = 22/24 with available brain MRIs), eight (36%) and one (5%) had hypoplasia and agenesis of the corpus callosum, respectively. Furthermore, only 2 of 12 individuals with the distal duplication breakpoints before base pairs 32,000,000 had hypoplasia of the corpus callosum. Of the individuals whose distal duplication breakpoints were after base pairs 37,000,000 (n = 23/25 with available brain MRIs), 8 (35%) had hypoplasia and 13 (57%) had agenesis of the corpus callosum.

Other neurological issues

Most individuals across all 8p subgroups had at least one neurological finding (TableS1). Generalized or truncal hypotonia was the most common neurological finding in all subgroups; however, it was more frequent and severe in individuals with invdupdel(8p) (Table1 and S1). Hypotonia was accompanied by hypertonia, prominently in the lower extremities, later in life. Microcephaly was common in individuals with del(8p)_proximal. Only two individuals each with invdupdel(8p) and del(8p)_proximal&distal had microcephaly. Macrocephaly was reported in five individuals with invdupdel(8p); however, three of them had hydrocephalus/ventriculomegaly on brain MRI. Among the other less commonly reported neurological issues were developmental regression, gait difficulties, and tremors (TableS1).

Neurobehavioral issues

Neurobehavioral issues were among the major concerns in individuals with del(8p) compared to individuals with invdupdel(8p) (Table1). Stereotypic behaviors and attention problems (attention deficit disorder [ADD], attention deficit–hyperactivity disorder [ADHD], hyperactivity) were the most commonly reported neurobehavioral issues in individuals with invdupdel(8p) and del(8p), respectively. Autism and autism spectrum traits, aggressivity/tantrums/impulsivity, sensory processing issues, echolalia, and anxiety were also commonly reported neurobehavioral issues (TableS1).

Congenital heart defects

Deleterious variants in GATA4 on 8p23.1 are a known cause of congenital heart defects (CHD), particularly atrial septal defect (ASD) (MIM 607941), ventricular septal defect (VSD) (MIM 614429), atrioventricular septal defect (ASVD) (MIM 614430), and tetralogy of Fallot (ToF) (MIM 187500). All individuals with deletions encompassing GATA4 were found to have an ASD and/or VSD (TableS1). In addition to the septal defects, pulmonic stenosis (PS) was also reported in 75% of individuals with GATA4 deletions. None of the individuals with VSD and PS in del(8p) subgroups was reported to have other components of ToF (misplaced/overriding aorta and right ventricular hypertrophy).

In recent years, SOX7 (within del[8p]_proximal interval) has also been proposed to be associated with CHD and congenital diaphragmatic hernia (CDH) [12,13,14]. While deletions of 19 individuals with del(8p)_proximal and del(8p)_proximal&distal encompass both GATA4 and SOX7, in two individuals with del(8p)_proximal&distal only SOX7 was deleted, and only one of these individuals who was born at term had a small patent ductus arteriosus. Additionally, both genes were duplicated in two individuals with reciprocal dup(8p)_proximal, and they were reported to have bicuspid aortic valve only. Of the 29 individuals whose deletions (n = 21) or duplications (n = 8) encompass SOX7, only 1 individual with del(8p)_proximal had CDH.

Both GATA4 and SOX7 were copy-number neutral in all individuals with invdupdel(8p) or del(8p)_distal. However, VSD and/or ASD were reported in over one third of individuals with invdupdel(8p) (n = 15, 38%), while no individual with del(8p)_distal was reported to have VSD and/or ASD. Additionally, patent foramen ovale (PFO) was also reported in seven individuals with invdupdel(8p) (18%), while no individual with del(8p) was reported to have PFO (TableS1).

In terms of CHD severity, structural heart defects tend to be minor and close spontaneously in individuals with invdupdel(8p) (n = 19/26 = 73%) compared to individuals with del(8p)_proximal and del(8p)_proximal&distal (n = 4/16 = 25% in total) (data not shown). Of the four individuals with dup(8p)_proximal, two individuals from our cohort and two individuals from the literature were not reported to have had surgical repair. Among other less commonly reported cardiac defects across all individuals were dextraposition of great arteries, double outlet right ventricle, hypoplastic right heart, coarctation of aorta, aortic stenosis, aortic regurgitation, ascending aorta dilation, mitral valve prolapse, enlarged heart, and arrhythmia (TableS1).

Other organ systems and facial features

Other organ system abnormalities such as visual, gastrointestinal, musculoskeletal, genitourinary, immunological, dental, and sleep issues were also variably reported across all individuals (Table1 and TableS1).

Figure3 shows facial images of 11 individuals with various chromosome 8p rearrangements. Dysmorphic facial features in individuals with invdupdel(8p) include smaller head circumference, large and prominent forehead, mildly arched eyebrows, deep-set eyes, ptosis or hooded eyelids, full cheeks, wide mouth, and micrognathia (Fig.3c, d, e). In individuals with del(8p)_proximal&distal (Fig.3g, h, i), there are no distinctive facial features although rounded face, large forehead, full cheeks, low hanging columella, and minor dental issues can be appreciated. Individuals with del(8p)_proximal and dup(8p)_proximal do not have major dysmorphic facial features.