Autism associated with 12q (12q24.31-q24.33) deletion: further report of an exceedingly rare disorder

Jaime Lin Gigliolle Romancini de Souza-Lin Fernanda Coan Antunes Letícia Burato Wessler Emílio Luiz Streck Cinara Ludvig Gonçalves About the authors

ABSTRACT

Chromosomal abnormalities are responsible for several congenital malformations in the world, some of these are associated to telomeric/subtelomeric deletions. The abnormalities involving the telomere of chromosome 12 are rare, with few reports of deletions involving 12q24.31 region in the literature, and, to our knowledge, only four of them in the 12q24.31-q24.33 region. We report a further case of interstitial deletion of bands 12q24.31-q24.33 associated with autism spectrum disorder. A 2-year-old boy with global developmental delay associated with multiple congenital anomalies. The Human Genome CGH Microarray 60K confirmed the diagnosis of 12q deletion syndrome. This study made a review of the current literature comparing our patient with previously reported cases. These detailed analyses contribute to the development of genotype/phenotype correlations for 12q deletions that will aid in better diagnosis and prognosis of this deletion.

Chromosome aberrations; Nervous system malformations; Developmental disabilities; Autism spectrum disorder; 12q24.31 deletion syndrome

RESUMO

Anomalias cromossômicas são responsáveis por inúmeras malformações congênitas no mundo, algumas delas associadas a deleções teloméricas/subteloméricas. As anomalias que envolvem o telômero do cromossomo 12 são raras, com poucos relatos na literatura sobre deleções relacionados à região 12q24.31 e, até onde sabemos, apenas quatro deles na região 12q24.31-q24.33. Relatamos um outro caso de deleção intersticial das bandas 12q24.31-q24.33 associada ao transtorno do espectro do autismo. Trata-se de um menino de 2 anos de idade com atraso global no desenvolvimento associado a múltiplas anomalias congênitas. A utilização do Human Genome CGH Microarray 60K confirmou o diagnóstico da síndrome de deleção 12q. Este estudo fez uma revisão da literatura atual, comparando nosso paciente com casos previamente relatados. Estas análises detalhadas contribuem para o desenvolvimento de correlações genótipo/fenótipo para deleções 12q, que ajudam aos melhores diagnóstico e prognóstico desta deleção.

Alterações cromossômicas; Malformações do sistema nervoso; Deficiências do desenvolvimento; Transtorno do espectro autista; Síndrome de deleção 12q24.31

INTRODUCTION

Alteration of gene dosage due to gains or deletions of large genomic regions causes many genetic disorders, which are frequently associated with intellectual disability, autism spectrum disorders (ASD) and other phenotypic findings.(11. Park HR, Lee JM, Moon HE, Lee DS, Kim BN, Kim J, et al. A short review on the current understanding of autism spectrum disorders. Exp Neurobiol. 2016;25(1):1-13. Review.)

Autism spectrum disorder is a set of neurodevelopmental disorders characterized by a deficit in social behaviors and nonverbal interactions, such as reduced eye contact, facial expression, and body gestures in the first 3 years of life. It is not a single disorder, and it is broadly considered to be a multi-factorial disorder resulting from genetic and non-genetic risk factors and their interaction. Although very complex and heterogenic, ASD is a strongly genetic disorder.(11. Park HR, Lee JM, Moon HE, Lee DS, Kim BN, Kim J, et al. A short review on the current understanding of autism spectrum disorders. Exp Neurobiol. 2016;25(1):1-13. Review.)

Among the most commonly employed techniques to detect ASD susceptibility genes, comparative genomic hybridization (CGH) technology has been widely used in research studies and in clinical practice of ASD, in order to detect copy number variants (CNV) throughout the genome. Copy number variants represent a significant source of genetic variability and are responsible of disease susceptibility for several neurobehavioral phenotypes.(22. Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L, Skaug J, et al. Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet. 2008;82(2):477-88.)

Some genetic anomalies causing several congenital malformations are associated to telomeric/subtelomeric deletions. Among these, chromosome 12q telomeric/subtelomeric deletions are rare and only few patients have been reported previously presenting small interstitial deletion of bands 12q24.31-q24.33, with no other karyotypic abnormalities.(33. Al-Zahrani J, Al-Dosari N, AbuDheim N, Alshidi TA, Colak D, Al-Habit O, et al. Chromosome 12q24.31-q24.33 deletion causes multiple dysmorphic features and developmental delay: First mosaic patient and overview of the phenotype related to 12q24qter defects. Mol Cytogenet. 2011;4:9.

4. Niyazov DM, Nawaz Z, Justice AN, Toriello HV, Martin CL, Adam MP. Genotype/phenotype correlations in two patients with 12q subtelomere deletions. Am J Med Genet A. 2007;143A(22):2700-5.

5. Plotner PL, Smith JL, Northrup H. Deletion 12q: a second patient with 12q24.31q24.32 deletion. Am J Med Genet A. 2003;118A(4):350-2.
-66. Sathya P, Tomkins DJ, Freeman V, Paes B, Nowaczyk MJ. De novo deletion 12q: report of a patient with 12q24.31q24.33 deletion. Am J Med Genet. 1999;84(2):116-9.)

We report the case of a patient with interstitial deletion of bands 12q24.31-q24.33 and review the current literature, comparing with previously reported cases, including other few cases of deletion involving 12q24.31 region.

CASE REPORT

A 2 year-old boy presented to pediatric neurology investigation due to global developmental delay associated with multiple congenital anomalies.

The patient was born from the first pregnancy of healthy, consanguineous (parents are first-degree cousins). At the time of pregnancy, the mother was 24-year-old and the father, 36 years old. No history of previous miscarriages, no report of use of prescribed or over-the-counter medicines, and no history of exposure to possible teratogenic products during pregnancy.

The pregnancy was complicated by ventricle enlargement detect by ultrasound at 5 months of gestation. The patient was born preterm, gestational age of 7 months, cesarean delivery. Birth weight was 1,720g (<3th centile), length was 39cm (<3th centile) and occipitofrontal circumference (OFC) was 31cm (<3th centile).

The patient was hospitalized four times at early infancy, twice due to pulmonary infection, once at 6 months of age for surgical removement of an extra toe on his left foot and for undescended testicles, and a last time, at 8 months, for a ventriculoperitoneal shunt surgery because of hydrocephalus.

Early global delay of developmental milestones was present. He kept the head up at the age of 12 months, sat at 16 months.

Currently, at 24 months, the patient presents failure to thrive, weight 10.6kg (5th percentile); length 78cm (<5th percentile) and OFC 48cm (50th percentile). Physical features were significant for large anterior fontanelle and slight coarsening of facial appearance. He had a short nose with anteverted nares and smooth philtrum (Figure 1). The ears were normally set and normal in size and configuration. Palate was narrow with thick gums. The patient also presented fifth-finger clinodactyly and polydactyly on the left foot (Figure 1).

Figure 1
Multiple congenital anomalies. (A) Slight coarsening of facial appearance, a short nose with anteverted nares and smooth philtrum. The ears were normally set and normal in size and configuration; (B) Fifth finger clinodactyly on hand; (C) Polydactyly on the left foot

The neurological evaluation was noteworthy for severe agitation associated with a self-aggressive behavior characterized by head banging leading to severe self-inflicted injuries. The patient presented spastic hypertonus and brisk tendon reflexes, being unable to walk independently or speak.

Cranial magnetic resonance imaging revealed supratentorial hydrocephalus, ballooning of the chiasmatic recess, corpus callosum thin, dilatation of the lateral ventricles and of the third ventricle, absence of septum pellucidum, and cerebral hypomyelination (Figure 2).

Figure 2
Magnetic resonance imaging T2-weighted sagital image. (A) Aqueductal web (arrow) with supratentorial hydrocephalus and ballooning of the chiasmatic recess. The corpus callosum was thin. Magnetic resonance imaging T2-weighted coronal image. (B) Axial image. (C) Dilatation of the lateral ventricles and of the third ventricle, septum pellucidum absence (arrow in C) and cerebral hypomyelination

The Human Genome CGH Microarray 60K (Agilent Technologies™) revealed an terminal deletion, starting from the middle of 12q24.31, between the genomic positions (123.309.075bp) to the near end of the q arm (132.283.607bp), arr[NCBI36/Hg18] 12q24.31-q24.33(123.309.075-132.283.607)X1, confirming the diagnosis of 12q deletion syndrome. The exam was performed in 2011 by the Human Genome Studies Center (Institute of Biosciences – Universidade de São Paulo).

DISCUSSION

Technological advances in epidemiological and molecular genetics have led recently to new findings in the field of the genetics of neuropsychiatric disorders. These new findings concern also the domain of the genetics of autism and have broaden current knowledge on the genetic disorders associated with ASD.(11. Park HR, Lee JM, Moon HE, Lee DS, Kim BN, Kim J, et al. A short review on the current understanding of autism spectrum disorders. Exp Neurobiol. 2016;25(1):1-13. Review.)

The number of known genetic disorders associated with ASD has increased with the use of array comparative genomic hybridization (aCGH). Such genetic diversity associated with similar autism cognitive-behavioral phenotypes created the concept of “syndromic autism” or “complex autism” (autism associated with genetic disorders/genetic syndromes), which qualifies individuals with at least one dysmorphic feature/malformation or severe intellectual disability. It is opposed to the concept of “non-syndromic autism” or “simplex”/“pure”/idiopatic autism (isolated autism) which qualifies individuals with moderate intellectual disability to normal cognitive functioning and no other associated signs or symptoms.(22. Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L, Skaug J, et al. Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet. 2008;82(2):477-88.)

The genetic investigation of such syndromic autism cases may lead to the recognition of rare and/or underreported diseases. Among these chromosome abnormalities, 12q24.31-q24.33 telomeric/subtelomeric deletions are rare and only a few patients have been reported previously.(33. Al-Zahrani J, Al-Dosari N, AbuDheim N, Alshidi TA, Colak D, Al-Habit O, et al. Chromosome 12q24.31-q24.33 deletion causes multiple dysmorphic features and developmental delay: First mosaic patient and overview of the phenotype related to 12q24qter defects. Mol Cytogenet. 2011;4:9.)Table 1 summarizes the main clinical findings of the previously reported cases.

Table 1
Clinical summary of cytogenetic abnormalities involving 12q telomere deletions

Our patient has some phenotypic findings that match from those presented in other patients with 12q deletions, as developmental delay, coarse face, growth failure, large anterior fontanella, delayed language development and clinodactyly. There was only one study indicating that parents were first cousins, which was also observed in the history of our patient. These findings detailed contribute to the development of genotype/phenotype correlations for 12q deletions and comparison with additional patients will continue to add to this clinical description.

The deleted region contains 52 annotated genes. Among these P2RX2 and ACADS are noteworthy for the developmental delay and behavioral and social problems presented in our patient.

CONCLUSION

Detailed findings of rare syndromes contribute to the development of genotypic/phenotypic correlations for 12q deletions, and the comparison with additional patients will continue to add to this clinical description. Genetic investigation of cases of syndromic autism may lead to the recognition of rare and/or unreported diseases.

We emphasize the importance of genetic analysis for the investigation of chromosomal abnormalities in patients with intellectual disability, dysmorphism, developmental delay and multiple congenital anomalies.

REFERENCES

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Publication Dates

  • Publication in this collection
    17 June 2020
  • Date of issue
    2020

History

  • Received
    18 Aug 2019
  • Accepted
    29 Nov 2019
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