Background

Autism Spectrum Disorders (ASD) now encompass a broad heterogeneous group of people who present in the early developmental years with a wide range of social and communication deficits, which are typically also associated with complex repetitive behaviors and circumscribed interests [1].

With the advent of genomic technologies, studies have recently demonstrated that there is a strong heritability in ASD, as well as a positive interplay among genetic and environmental factors in the etiology of social deficits and unusual behaviors [2, 3]. Moreover, a high (60 to 90 %) concordance rate in monozygotic twins for ASD has been already determined [4].

The accumulation of these data overtime made a distinction between idiopathic (Non-syndromic) ASD and syndromic ASD possible. From Mendelian inheritance to de novo SNV and CNV point mutations [2] many genes are now believed to be implicated in the role of a neuronal molecular level activity [5]. These genes have also accounted for the neurobiological changes in part of the brain that affects social cognition, sensory perception and executive function [1, 6].

The trend toward linking autistic phenotypic behaviors to different genotypes is legitimate, but can be very unreliable due to changes in behavioral phenotype and developmental trajectories over time as individuals with ASD grow older [7].

The rarely reported terminal 12p deletion zone spectrum is a group of characteristic genotypes thought to be associated with autistic core features among other developmental, psychiatric, cancer predisposition and clinical phenotypic presentations [8–11].

The first report on the so-called “12p deletion spectrum” was published in 1975 by Magnelli and Therman [12, 13].

For clinical understanding purpose, the 12p regions can be divided into four group types according to the site of the interstitial deletion: 12p1-11; distantly extending deletions 12p11-13, 12p13 band, and the distal zone of 12p [14].

In this report, we present a new case of a 4-year-old with ASD and a 12p13.2 deletion, and further discuss the relationship of the condition to the phenotypic spectrum of the 12p region, by illustrating examples taken from the literature.

The target goal here is to heighten readers’ perception into the trend to personalize the distinct autistic and related developmental conditions encompassing the 12p region.

Methods

Patient recruitment

We recruited a 4-year-old boy diagnosed with developmental arrest and ASD due to an underlying 12p deletion for this report. Permission by the child’s mother has been granted through an informed consent, which has been approved by the SARAH Network Institutional Research Ethical Board under number 49915515.1.0000.0022.

A description of the case, as well as the results of the patient’s diagnostic tests has been undertaken below.

Review of the literature

We searched PubMed for all existent articles related to interstitial and terminal deletions in the 12p region. The terms 12p and autism were used for this search. Only articles written in English, French and German were considered for a review. Fifty-two relevant papers were further completely appraised.

Case Presentation

A 4-year-old male proband (Figs. 1, 2, 3) presented with global developmental delay noticed by his family when he was around 11 months of age. The child was born at term from a vaginal delivery and an uneventful pregnancy. His parents were non-consanguineous and healthy. The mother disclosed she had consumed alcohol for social purposes before being aware she was pregnant. She reports having drunk small beverages of beer during the week, as well as vodka throughout the weekends, until the third month of gestational period. The exact daily amount of alcohol consumption is unknown. Despite the fact the mother had a small amount of vaginal bleeding at 42 weeks of gestation, the child’s Apgar scores were 8 in the first and fifth minutes. The patient developed a mild, asymptomatic, hypoglycemia due to suction difficulties, but he was discharged from the hospital at day three of life and had been able to be breastfed until 3 months of age only.

Fig. 1
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Anterior view of patient´s face and body

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Fig. 2
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Lateral view of patient´s face and body

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Fig. 3
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Anterior view of patient´s face and body

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The child’s social and language skills were below the rest of his developmental domains. He attained independent walking by 23 months of age. Nevertheless, his verbal and non-verbal communication capabilities were so weak that, at that age, it was clearly observed that the quality of his eye contact, as well as social interactions, were in the autistic spectrum range. Moreover, significant motor and vocal stereotypic behaviors alongside difficulties in functional play and imitation had also ensued. The child’s growth curves for weight (centile 15–25), height (centile 15–25) and head circumference (centile 75) have been steadily unchanged over the course of his growth. No facial or corporeal dysmorphic features have been detected, that could be specific for FAS, or any specific genetic syndrome. In addition, there were no reports of clinical seizures in this patient. His physical and neurological examinations were unremarkable, except by the fact that he has developed a refraction error visual impairment. He was seen by an ophthalmologist who prescribed lenses accordingly.

At 3 years old, a brain MRI, which was undertaken to investigate the patient’s global developmental delays, showed no signs of abnormal patterns in myelination or in the setup of the structures comprising the supra and infratentorial brain compartments. However, we identified sparse increased signal in FLAIR and T2-weighted images in the white matter territories adjacent to the lateral ventricles bodies and subcortical zones (Figs. 4, 5, 6, 7). In addition, around the same period of time, a v-EEG demonstrated signs of a non-specific slow background, but no other abnormal electrographic activity had been identified (Fig. 8).

Fig. 4
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Brain MRI - Increased signal in T2-weighted images in the withe matter territories adjacent to the lateral ventricles bodies and subcortical zone

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Fig. 5
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Brain MRI - Increased signal in FLAIR images in the withe matter territories adjacent to the lateral ventricles bodies and subcortical zone

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Fig. 6
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Brain MRI - Increased signal in FLAIR images in the withe matter territories adjacent to the lateral ventricles bodies and subcortical zone

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Fig. 7
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Brain MRI - Increased signal in FLAIR images in the withe matter territories adjacent to the lateral ventricles bodies and subcortical zone

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Fig. 8
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EEG showing non specific slow background activity, as well as no epileptiform discharges

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Fragile X DNA screening, as well as metabolic screening for Inborn Errors of Metabolism results, all came back negative. Chromosome analysis was carried out (please, see below).

In order to reinforce our thoughts on the diagnosis of ASD related to the genotype found in this patient, we revisited the ASD diagnosis at the patient’s age of 4 years, according to the Childhood Autism Rating Scale (CARS) [15]. The overall CARS score was 44, suggesting that the child was in the severe range of the autistic spectrum. This finding confirmed our primary developmental diagnosis of ASD, which has finally been aligned to the novel DSM5 criteria.

Data analysis

A high resolution G-banded chromosome analysis of peripheral blood lymphocytes showed 46,XX,del(12p)(13.2) karyotype (550–600 GTW bands) in this patient.

The 12p13.2 deletion has not been identified in the parent’s karyotype, indicating a de novo terminal deletion in the short arm of chromosome 12.

We also used OMIM database to scrutinize scientific data related to all genes seated on the 12p13.2 region. Then, we selected the genes that could potentially be related to one of the etiologies of ASD.

Review of the Literature

Aside from the present patient, we found an additional number of 43 cases described in the medical literature since 1974, that have been related to the 12p region. However, to the best of our knowledge, none of the previous had been specifically linked to the 12p13.2 band. All cases were summarized in Table 1.

Table 1 Behavioral and clinical phenotypes in the 12p interstitial and distal deletion spectrum syndromes
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Discussion

In this report, we described a new case of a young male child with initial global developmental delay which turned out to become more specific of the typical core signs that underpin the diagnosis of ASD, as the child became a preschooler. These signs are characterized by deficits in social and communication capabilities associated with repetitive behaviors and activities plus circumscribed interests [1].

According to recent analysis, it appears that there is a growing body of evidence pointing toward an increasing rate of ASD with a current average prevalence of 1 % worldwide [16]. The higher rates of ASD might be the by-product of a variety of factors, ranging from the heterogeneity in the diagnostic criteria and diagnostic practice, to changes in the epigenetic factors [3, 17, 18].

When it comes to the genetic influences on the etiology of ASD, one has to take into account the heterogeneity of genotypes, comprising roughly one thousand genes or so, that have been associated with autism. According to Butler et al. [19], routine cytogenetic studies typically identify abnormalities in chromosomes 2, 3, 4, 5, 7, 8, 11, 13, 15, 16, 17, 19, 22 and X. Those findings include deletions, duplications, translocations and inversions involving specific chromosome regions where known candidate ASD genes are seated [19]. Noteworthy, even considering the fact that this is an updated publication, the 12p deletion spectrum is still not mentioned as a common site for genes related to ASD. Moreover, according to McDonald et al. [20], aside from the gene-enriched subtelomeric regions in these most common sites, 1p, 22q, 4p, 9q, 8p, 2q and 20p, respectively outlined here in order of frequency, there have been only a few reports involving the short arm of the chromosome 12. Table 1 illustrates all patients with the interstitial and terminal 12p deletions previously described since the first publications in 1974.

In any case, our 4-year-old patient has a genetic setup in 12p region that, to best of our knowledge, has not yet distinctively been presented in the literature. That also includes the fact that this patient lacked the variable dysmorphic features frequently presented in the majority of related papers as listed in Table 2. In addition, although data on ASD was not available in many of the outlined cases in Table 1, aside from the present child, three of others displayed were described as having ASD. Noteworthy, this child is the only one of the four who did not display significant dysmorphic features.

Table 2 Frequent dysmorphic signs and associated congenital anomalies previously described in the 12p deletion syndrome
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On the other hand, there are other previously published reports on sporadic ASD originated from an NMDA-related gene, named GRIN2B, that is located in 12p13.1. However, those cases were related to point mutations and translocations as opposed to deletions occasionally found in the 12p region [21–23].

At this point, one might also inquire about some of the risk factors for a brain injury this child had, such as, for instance, antenatal exposure to alcohol and hypoglycemia during the child’s initial hours of life. Indeed, according to a recent meta-analysis from Tsang et al., the alcohol exposure could partially be accounted for the appearance of atypical behavioral, social and cognitive difficulties [24]. Moreover, the fact that the child did not present with the FAS features does not rule out the broader, secondary diagnosis of FASD, which comprises FAS, pFAS, ARND and ARBD [25].

On the other hand, as there are no reliable biological markers today to rule in or out FASD, we can only say at this point that, taking into account the previously described literature on the relationship between ASD and the 12p deletion spectrum, the former might well be at least partially considered as the causative factor for this child’s ASD diagnosis. Furthermore, the patient’s brain MRI findings are non-specific and the increased signal in FLAIR and T2-weighted images might most likely be related to zones of terminal myelination, rather than a lesion caused by alcohol and/or the minor asymptomatic neonatal hypoglycemic episode.

We acknowledge there is a technical limitation in our report due to the lack of specific laboratory expertise and materials. We have not been able to pursue further investigations in this child using more sophisticated techniques, such as the aCGH arrays. This hampered our understanding in which genes were missing in the 12p13.2 of our affected patient.

Nevertheless, when looking up into the 12p13.2 region on the OMIM database, we were able to identify relevant genes related to Homo sapiens (human) species, as outlined in Table 3.

Table 3 Distribution of genes located in the 12p region
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If one takes into account the theoretical factors (synaptogenesis, synaptic connectivity, dendritic spines formation and maintenance, neuronal membrane protein turnover and related neurotransmitters metabolism, as well as immunological issues) related to the pathogenesis of ASD, from the genes directly linked to humans, as enlisted in Table 3, one finds it important to observe that TNFRSF1A [26], LRP6 [9, 27], CLEC7A [28], GABARAPL1 [29], CLEC1B [30], STYK1 [31], CLEC12A [32], CLEC1A [33], MAGOHB [34], could be potentially involved in the pathogenesis of ASD, due to their anti-inflammatory, immunologic and neuro trafficking roles. However, given our limitation to further assess these data, more extensive and in-depth research is needed in that regard.

Below we describe some of the already known variations of clinical presentation in the 12p deletion spectrum that might be related to ASD.

The 12p11.1-p12.1 interstitial deletion

In the report of Soysal et al. [12], a very distinctive phenotype is observed in a 12 years old girl with a karyotype 46,XX, del(12)(p11.1-p12.1). This patient, born from a young unrelated couple with an unremarkable family history, presented with dysmorphic craniofacial features (microcephaly, ocular hypertelorism, down-slanting palpebral fissures, strabismus, myopia, minor inner epicantal folds, arched eyebrow, broad nasal base, bulbous nose, short philtrum, microretrognathia, irregular tooth alignment), corporeal dysmorphic features (distal phalangeal abnormalities, 5th finger camptodactily, brachydactyly of the feet, scolioses and joint hyper mobility), ID and ASD. The most important genes seated in that region are PKP2, ALG10, KRAS, FGD4, PTHLH, DNM1L. However, an additional 0.191 MB deletion in 2p16.3 was found using aCGH microarray. NRXN1 is considered the most significant gene in this region. According to Soysal et al. [12], the role of neurexin genes in synaptogenic activities has been previously attributed as a cause of ASD as well as other developmental and psychiatry disorders. The social deficits and behavioral abnormalities in this patient could most likely be a combination of influences coming from both regions. Therefore, a clear understanding in the role of deletion 12p11.1-p12.1 on ASD and related developmental disorders is not fully doable in this case.

The 12p13.1 interstitial deletion

Dimassi et al. [35] reported on 3 intellectually disable patients with 12p13.1 deletions. The molecular findings had been initially investigated with aCGH technique and posteriorly confirmed via FISH and qPCR tests. Overall, they consisted in deletion of exon 1 and exon 2 of GRIN2B. This gene encodes the NR2B subunit of NMDA receptors, known to play a role in corticogenesis, neuronal migration and synaptogenesis during brain development. According to Dimassi et al. [35], there have been a few other reports in patients with ASD and ID but no facial dysmorphic features (oval-shaped face, arched eyebrows, almond-shaped palpebral fissures, long philtrum, everted vermillion border of the lower lip and broad chin) were noticed. In their paper, according to the description of their 3 patients (Table 1), one was considered autistic and 3 intellectually disabled. Furthermore, it is noteworthy to mention that only one also presented with seizures.

The 12p13.33 distal subtelomeric deletion

In 2010, McDonald et al. [20] described a 40 week term baby born from non-consanguineous parents with an unremarkable family history, and after an uneventful pregnancy. At the age of 6 years, microcephaly, short nose, prominent ears were detected. In addition, the child had cognitive and social difficulties. Despite having tested with a normal karyotype, an MLPA test was further carried on using SALSA P070 kit (MRC Holland). The results indicated a deletion in the subtelomeric region, which was further confirmed by FISH and aCGH tests. The later revealed a 2.95 MB deletion in the region comprised of 36 genes, 16 of which having clinical significance according to OMIM. Although a more detailed description of the patient’s social and behavioral difficulties is lacking in this report, it appears as though this child could potentially meet clinical criteria for the diagnosis of ASD, but this information is presumptive and not subject to a reliable confirmation at this time.

Recently, another group of acknowledged genetic researchers from Brazil published a report of an 8-year-old male patient, who was also born with spina bifida [8]. The child was diagnosed with ASD by age 2,5 years. At that time, the diagnosis was made on the basis of the former DSM-IV-TR criteria and had also been sustained by the CARS. This boy had a 1.5 Mb microdeletion in 12p13.33 zone, which encompasses 13 genes, one of them, the ERC1, a 500 kb gene known to molecularly regulate neuroplasticity and neurotransmitters in a presynaptic level [8, 36]. By comparing previous reports [36, 37] of patients and taking into account the implications of synaptic dynamics over the casual course of ASD, Silva et al. raised awareness to the role of ERC1 as part of the growing body of genes that can potentially be accounted for the etiology of ASD [8].

Conclusion

The 12p deletion spectrum is rarely described as part of the selective genotypes thought to be related to ASD. Even inside of a small piece of the puzzle, there might be ample variation in the behavioral and clinical phenotypes of children and adults presenting with this particular genetic profile.

In that regard, the particular 12p13.2 distal deletion presentation is one of the possible genotypes encompassed by the “12p deletion spectrum syndrome”, that might potentially be connected to the diagnosis of ASD and related developmental disorders.

Due to their role in the inflammatory, immunologic and neuro trafficking routes, the genes TNFRSF1A, LRP6, GABARAPL1, CLEC1B, STYK1, CLEC12A, CLEC1A, MAGOHB, and CLEC7A, that comprise part of 12p13.2 band, might potentially play a role in the pathogenesis of ASD. More extensive research is needed to clarify the later.