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

Introduction

Changes in gene dosage due to the gain or deletion of large genomic regions are the cause of many genetic disorders . They are often accompanied by phenotypes such as intellectual disability and autism spectrum disorder (ASD) ⁽¹⁾ .
Autism spectrum disorder is a set of neurodevelopmental disorders characterized by a lack of social behavior and nonverbal interaction. A set of neurodevelopmental disorders characterized by a lack of social behavior and nonverbal interaction. A set of neurodevelopmental disorders characterized by a lack of social behavior and nonverbal interaction (within the first 3 years of life). Not a single disorder Rather than a single disorder, it is broadly considered to be a multifactorial disorder caused by genetic and nongenetic risk factors. It is widely considered to be a multifactorial disorder caused by genetic and nongenetic risk factors and their interactions. ASD is a very complex and heterogeneous disease, but it is a highly heritable disease ⁽¹⁾ .
Among the techniques for detecting susceptibility genes for ASD, comparative genomic hybridization (CGH) techniques are widely used in ASD research and clinical settings to detect copy number variations (CNVs) on the genome. Copy number variants are an important source of genetic diversity and are responsible for disease susceptibility of several neurobehavioral phenotypes ⁽²⁾ . Some genetic abnormalities
that cause congenital malformations are associated with telomeric or subtelomeric deletions . Among them, telomeric/subtelomeric deletions of chromosome 12q are rare, and only a few patients with small stature have been reported to date. Telomeric/subtelomeric deletions of chromosome 12q are rare, and only a few patients with small stature have been reported to date with interstitial deletion of band 12q24.31-q24.33 without other karyotypic abnormalities. ^(3-6) We report a case of a patient with an interstitial deletion of band 12q24.31-q24.33. We report a case of a patient with an interstitial deletion in band 12q24.31-q24.33 and review the current literature.We report a patient with an interstitial deletion in band 12q24.31-q24.33 and compare the case with previously reported cases, including several other cases of deletions involving the 12q24.31 region.

Case report

A 2-year-old boy was admitted to a pediatric neurological examination because of global developmental delay associated with multiple congenital anomalies.
The patient was born from a first pregnancy in a healthy consanguineous family (parents were first-degree cousins). At the time of conception, the mother was 24 years old, and the father was 36 years old. There was no history of miscarriage, no reported use of prescription or over-the-counter medications, and no exposure to teratogens during pregnancy.
The pregnancy was complicated by ventricular enlargement detected by ultrasound at 5 months of gestation. Preterm labor was achieved at 7 months of gestation, with delivery by cesarean section. Birth weight was 1,720 g (<3rd centile), length 39 cm (<3rd centile), and occipital-frontal circumference (OFC) 31 cm (<3rd centile).
The patient was hospitalized four times during early infancy, twice for pulmonary infections, once at 6 months for surgical removal of an extra toe on the left foot and cryptorchidism, and finally once at 8 months for ventriculoperitoneal shunt surgery for hydrocephalus.
Early global delays in developmental milestones were noted. He held his head up at 12 months of age and sat at 16 months.
Now, at 24 months of age, the patient presents with failure to thrive, weight 10.6 kg (5th percentile), length 78 cm (below the 5th percentile), and OFC 48 cm (50th percentile). Physical characteristics were significant for a large anterior fontanel and slight coarsening of the facial appearance. The nose was short with anteverted nostrils and smooth hyphae ( Figure 1-A ). The ears were normally set and of normal size and shape. The palate was narrow with thick gums. The patient also presented with clinoid digits and polydactyly of the fifth digit on the left foot ( Figure 1-B,C ).

Figure 1. Multiple congenital anomalies.

(A)Slight coarsening of the face, anterior tilt of the nostrils, smooth friendliness. Ears were normally set, normal in size and shape

Neurological evaluation was notable for severe agitation associated with autoaggressive behavior characterized by head bumps resulting in severe self-injury. The patient presented with spastic hypertonia and brisk tendon reflexes and was unable to walk or speak independently.
Head magnetic resonance imaging revealed supratentorial hydrocephalus, ballooning of the optic chiasmatic recess, a thin corpus callosum, dilated lateral and third ventricles, absent septum pellucidum, and cerebral hypomyelination (Figure 2) .

Figure 2. Magnetic resonance imaging, T2-weighted sagittal image. The corpus callosum was thin. Magnetic resonance imaging, T2-weighted coronal image.

The human genome CGH microarray 60K (Agilent Technologies™) revealed a terminal deletion starting in the middle of 12q24.31 from genomic position (123.309.075bp) to the proximal end of the q-arm (132.283.607bp), arr[NCBI36/Hg18]12q24.31-q24.33(123.309.075-132.283.607)X1, which led to the diagnosis of 12q deletion syndrome . This study was performed by the Human Genome Research Center (Institute of Biological Sciences-University of São Paulo) in 2011.

The number of known genetic disorders associated with ASD is increasing with the use of array comparative genomic hybridization (aCGH). Such genetic variability associated with similar autistic cognitive behavioral phenotypes has given rise to the concept of “syndromic autism” or “complex autism” ( autism associated with genetic disorders/genetic syndromes ), which qualifies individuals with at least one morphological abnormality/malformation or severe intellectual disability. This contradicts the concept of “nonsyndromic autism” or
“simple”/“pure”/“idiopathic autism (isolated autism),” which means that individuals with moderate intellectual disability have normal cognitive function and no other associated signs or symptoms. ⁽²⁾
Genetic testing of such syndromic autism cases may lead to recognition of rare and/or underreported diseases. Among these chromosomal abnormalities , 12q24.31-q24.33 telomeric/subtelomeric deletions are rare, and the main clinical findings of previously reported cases are summarized in Table 1.
Our patient has several phenotypic findings consistent with those presented in other patients with 12q deletion , including developmental delay, coarse face, growth failure, large anterior fontanel, delayed speech development, and clinodactyly. Only one study showed that the parents were first cousins, which was also observed in our patient’s medical history. These findings contribute in detail to the expression of genotype/phenotype correlations for 12q deletion , and comparisons with additional patients will continue to add to this clinical description. The
deleted region contains 52 annotated genes. Of these P2RX2 and ACADS, the developmental delay and behavioral and social problems presented in our patient should be noted.

Conclusion

Further detailed findings of rare syndromes contribute to the development of genotype/phenotype correlations for 12q deletions , and comparisons 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 disorders. The authors emphasize the importance of genetic analysis for the study of chromosomal abnormalities
in patients with intellectual disability, dysmorphism, developmental delay and multiple congenital anomalies .

Observations

Technological advances in epidemiological and molecular genetics have recently provided new insights into the genetics of neuropsychiatric disorders. These new insights also have implications for the area of ​​autism genetics, expanding our current knowledge of genetic disorders associated with ASD ⁽¹⁾ .

Author Information

Lin J: http://orcid.org/0000-0002-7433-6231Sousa-Lin
GR: http://orcid.org/0000-0001-9930-7288Antunes
FC: http://orcid.org/0000-0001-5571-3321Wessler
LB: http://orcid.org/0000-0001-6700-0396Streck
L: http://orcid.org/0000-0002-2859-4678Gonalves
CL: http://orcid.org/0000-0003-2468-8885

References

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Table 1. Clinical summary of cytogenetic abnormalities associated with 12q telomeric deletions

IGF-1: insulin-like growth factor-I; ID: intellectual disability; VSD: ventricular septal defect; ASD: atrial septal defect.