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Childhood-onset autosomal recessive ataxias: a cross-sectional study from Turkey

  • Hatice Mutlu-AlbayrakEmail author
  • Emre Kırat
  • Gürkan Gürbüz
Original Article

Abstract

Autosomal recessive ataxias (ARAs) are a heterogeneous group of inherited neurodegenerative disorders that affect the cerebellum, the spinocerebellar tract, and/or the sensory tracts of the spinal cord. This study is aimed at establishing molecular classification and phenotypic correlation of childhood-onset ARAs in Southeast Anatolia of Turkey. Sixty-five children (aged 0 to 18) from 40 unrelated families who were analyzed through hereditary ataxia NGS panel between the years of 2015–2018 were selected for the study. Seventeen different, clinically significant ARA-related pathogenic variants were detected in 33 of 40 families (82.5%), 12 of which were noted to be unreported variants. Among these 33 families, 24 had ATM-related (72.72%), four had SACS-related (12.12%), three had COQ8A-related (9.09%), and two had APTX-related (6.06%) pathogenic variants. The c.3576G>A (p.K1192=) was the most common homozygous pathogenic ATM variant (33.33%) that was associated with milder phenotype of ataxia telangiectasia (AT) with the onset of age of 3. Patients with SACS variants demonstrated developmental delay and progressive ataxia before the age of 3. Slowly progressive ataxia and intellectual disability were the common clinical manifestations of the patients with homozygous c.1396delG (p. E466Rfs*11) pathogenic variant in COQ8A. Homozygous APTX c.689T>G (p.V230G) pathogenic variant was identified in two patients who had chief complaint of ataxic gait onset after puberty. The most common types of ARAs in this region are AT- and Charlevoix-Saguenay-type spastic ataxia. ATM gene analysis should be performed foremost on children presenting early-onset ataxia from Southeastern Anatolia. If there is a concomitant peripheral neuron involvement, SACS gene analysis should be preferred. This valuable data will be a guide for the first step molecular diagnostic approach before requesting the NGS panel for ARA.

Keywords

Hereditary autosomal recessive ataxias Southeast Anatolia NGS 

Introduction

Autosomal recessive ataxias (ARAs) are a group of inherited neurodegenerative disorders that affect the cerebellum, the spinocerebellar tract, and/or the sensory tracts of the spinal cord. Estimated overall prevalence is 3–6/100,000 in Europe [1]. As ARAs are heterogeneous and disorganized diseases, a classification system has been published in 2019 in order to classify ARAs and the general approach principles to patients presenting with ataxia [2]. According to this classification, the first step in evaluating a patient with ataxia is to perform a detailed clinical evaluation that includes a clinical history, a family history, a targeted neurological and systemic physical evaluation, and relevant clinical tests. Following the clinical assessment, it should be verified that acquired and treatable causes for ataxia have been excluded. Once acquired causes have been ruled out, a genetic etiology may be considered, especially in the presence of a positive family history, early onset, and chronic progressive course.

In the past few years, next-generation sequencing (NGS) has provided an unprecedented increase in our ability to sequence large numbers of genes at an equivalent cost to traditional Sanger sequencing. NGS has led to the identification of new ARA-causing genes or novel phenotypes of known ARA-causing genes, improving the most common ARAs which are usually of childhood-onset [3].

Molecular classification and phenotypic correlation of childhood-onset ARAs have not been previously reported in Turkey, especially Southeast Anatolia. Here, we aim to review the patients with childhood-onset ARAs whose diagnoses were molecularly confirmed by hereditary ataxia NGS panel to determine the genotypic features, make phenotypic correlation, and present the relative frequency of the ARAs in Southeast Anatolia of Turkey.

Materials and methods

Profile of patients

Sixty-five children (aged 0 to 18) from 40 unrelated families who were analyzed through hereditary ataxia NGS panel between the years of 2015–2018 were selected for the study.

Patients were selected based on the following criteria: (1) presenting primarily childhood-onset progressive ataxia, having family history in which only sibs are affected (i.e., single generation in the family), and/or with consanguineous parents suggesting autosomal recessive (AR) inheritance and (2) neurologic examination including gait disturbance and dysmetria, often associated with dysarthria and tremor associated with a sign of cerebellar atrophy in magnetic resonance imaging (MRI).

Patients with acquired causes, metabolic diseases (aminoacidopathies, organic acidemias, lysosomal storage disorders, and peroxisomal biogenesis defects), and complex phenotypes of which ataxia is a secondary or late feature had already been ruled out by the pediatric neurologists before referring to the genetic diagnosis center.

Genetic analysis

Genomic DNA was extracted from whole blood samples using an automated method (RSC Whole Blood DNA Kit) in the Maxwell® 16 (Promega Corporation, Madison, WI) and sequenced using a custom-designed targeted panel that comprised all exons and exon-intron junctions of ABCB7, COQ8A, APTX, ATM, C12ORF65, POLG, SACS, SETX, SLC2A10, SLC52A2, SLC52A3, TACO1, and TTC19 on the Ion Torrent System (Thermo Fisher Scientific). Data was processed using the Ion Reporter Pipeline (Thermo Fisher Scientific) and annotated using IGV. Quality metrics assessed the performance of targeted panel sequencing. In this analysis, 96.8% of the reads were aligned to the reference genome with an average sequencing depth of 1315X on targeted regions. Variants were described using Human Genome Variation Society nomenclature guidelines and checked against those available in 1000 Genomes, dbSNP, ClinVar, and Human Genome Mutation Database. American College of Medical Genetics and Genomics Standards and Guidelines were used for determination of variant pathogenicity (if a variant falls within a known functional domain (per UniProt), then it is counted as pathogenic within the domain in order to trigger rule PM1. If there are at least ten known variants, and if 2/3 of them (66.7%) are pathogenic, then that will trigger rule PM1) [4]. Each new disease-causing variant, identified by data analysis, was also confirmed using direct Sanger sequencing with the BigDye™ Direct Cycle Sequencing Kit (Applied Biosystems™). Parental DNAs were also checked against the heterozygosity for each new disease-causing variant. Molecular diagnostic rate was calculated on the basis of the founder pathogenic variant even if it was identified in more than one member in a family.

Results

Review of the detected variants and related phenotypes

Seventeen different clinically significant ARA-related pathogenic variants were detected in 33 of 40 families (82.5%)—38/65 patients—12 of which were noted to be unreported variants. Among those 33 families, 24 had ATM-related (72.72%), four had SACS-related (12.12%), three had COQ8A-related (9.09%), and two had APTX-related (6.06%) pathogenic variants (Fig. 1).
Fig. 1

Flowchart showing the method and frequency graph of the variants

The c.3576G>A (p.K1192=) in the ATM gene was the most common—11/33 families (33.33%)—homozygous pathogenic variant that was identified. The related phenotypes were determined by putting together referred clinical information of the patients and other reported cases that were obtained through reviewing the literature [5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16] (Table 1). Patients with 3576G>A variant had milder phenotype (slowly progressive ataxia with/without telangiectasia and immune deficiency). The c.6188G>A (p.G2063E) variant was detected in two patients from unrelated families who presented ataxia and delayed walking. According to previous studies, this variant is not associated with increased cancer risk. Two patients from unrelated families with c.4236+4A>G (IVS28+4A>G) variant had immune deficiency and increased cancer risk. Another patient had c.103C>T (p.Arg35*) variant which was related to classical ataxia telangiectasia (AT) phenotype and breast cancer. The c.6047A>G (p.D2016G) variant was found in one patient who had milder phenotype with immune deficiency. One patient with c.6047A>G (p.D2016G)/IVS14-4A>G compound heterozygous variant was referred to us with classical AT phenotype. c.8585-15_8596del, c.2921+1G>A(IVS19+1G>A), c.4236+4A>G (IVS28+4A>G), c.312delC (p.Phe104Leufs*12), and c.8585_8611del were other identified pathogenic homozygous ATM variants which have not been previously reported. All these patients with novel variants had classical AT phenotype.
Table 1

Review of the detected variants and related phenotypes

Gene

Transcript

HGVS coding

HGVS protein

Coding impact

Number of patients (%)

Number of families (%)

References

Related phenotype

ATM

NM_000051.3

3576G>A

Lys1192=

Splicing

14 (50%)

11 (33.33%)

5–8

Milder phenotype

ATM

NM_000051.3

6188G>A

G2063E

Missense

2 (5.26%)

2 (6.06%)

9–11

Ataxia, delayed walking, without increased cancer risk

ATM

NM_000051.3

4236+4A>G

-

Splicing, intronic

2 (5.26%)

2 (6.06%)

12

Immune deficiency, increased cancer risk

ATM

NM_000051.3

103C>T

R35X

Nonsense

1 (2.63%)

1 (3.03%)

13–15

Classical A-T phenotype, breast cancer

ATM

NM_000051.3

6047A>G

D2016G

Missense

2 (5.26%)

2 (6.06%)

10, 16

Milder phenotype, immune deficiency

ATM

NM_000051.3

8585-15_8596del

-

Splice junction loss

1 (2.63%)

1 (3.03%)

NR

Classical A-T phenotype, immune deficiency

ATM

NM_000051.3

2921+1G>A

-

Splicing, intronic

1 (2.63%)

1 (3.03%)

NR

Classical A-T phenotype

ATM

NM_000051.3

4236+4A>G

-

Splicing, intronic

1 (2.63%)

1 (3.03%)

NR

Classical A-T phenotype

ATM

NM_000051.3

312delC

-

 

1 (2.63%)

1 (3.03%)

NR

Classical A-T phenotype

ATM

NM_000051.3

8585_8611del

-

Inframe

1 (2.63%)

1 (3.03%)

NR

Classical A-T phenotype

ATM

NM_000051.3

6047A>G/IVS14-4A>G

D2016G/-

Missense/intronic

1 (2.63%)

1 (3.03%)

10, 16/NR

Classical A-T phenotype

SACS

NM_014363.6

10441C>G

L3481V

Missense

1 (2.63%)

1 (3.03%)

NR

Progressive ataxia, DD

SACS

NM_014363.6

6822_6826delGTCAT

S2275Gfs*3

Frameshift

1 (2.63%)

1 (3.03%)

NR

Progressive ataxia, DD

SACS

NM_014363.6

6599A>T

D2200V

Missense

1 (2.63%)

1 (3.03%)

NR

Progressive ataxia, DD

SACS

NM_014363.6

7205_7206delTT

L2402Rfs*6

Frameshift

2 (2.63%)

1 (3.03%)

NR

Progressive ataxia, DD

COQ8A

NM_020247.5

1396delG

E466Rfs*11

Frameshift

4 (2.63%)

3 (9.09%)

NR

Milder phenotype, ID

APTX

NM_175073.2

689T>G

V230G

Missense

2 (2.63%)

2 (6.06%)

NR

Juvenile-onset ataxia

     

38 (100%)

33 (100%)

  

Classical A-T phenotype: progressive cerebellar ataxia, oculocutaneous telangiectasia; milder phenotype: slowly progressive ataxia

HGVS Human Genome Variation Society, NR not reported

Homozygous c.10441C>G (p.L3481V), c.6822_6826delGTCAT (p.Ser2275fs), c.6599A>T (p.D2200V), and c.7205_7206delTT (p.Leu2402Argfs) pathogenic variants in the SACS gene have not been reported previously. Progressive ataxia and developmental delay (DD) were the main clinical features of these patients.

All the patients with novel COQ8A homozygous c.1396delG (p.Glu466fs) pathogenic variant had slowly progressive ataxia accompanied by intellectual disability (ID). Other two patients from unrelated families who presented juvenile-onset ataxia had novel APTX homozygous c.689T>G (p.V230G) pathogenic variant.

Clinical manifestations of the selected cases with frequently detected variants

Detailed clinical characteristics of seven patients from six unrelated families with the most common variants were assessed (Table 2). Gait disturbance was the most frequent chief complaint in 3576G>A-related AT patients. The mean age of symptoms’ onset was 3. DD was reported in one of three patients. None of them had ocular telangiectasia or immune deficiency. Cerebellar atrophy was observed on cranial MRI in two of three patients (Fig. 1). Having onset of the symptoms before the age of 3, progressive ataxia, DD, and extracerebellar findings such as peripheral neuron involvement were the general features of the patients with SACS variants. Prominent cerebellar folia were detected on cranial MRI of a 5-year-old patient with SACS c.7205_7206delTT variant. On the other hand, a 10-year-old patient with SACS c.6599A>T variant had a significant cerebellar atrophy (Fig. 2). The age of symptoms’ onset was 5 in the patient with COQ8A c.1396delG variant. His main complaint was gait disturbance. Ataxia, dysmetria, tremor, and dysarthria were noted on neurological examination. He had also learning disability accompanied by hyperactivity and aggressive behavior.
Table 2

Clinical features of the selected cases with frequently detected variants

Case

Variant

Age

Gender

Chief complaint

Age of onset

Cerebellar findings

Extracerebellar findings

Neuromotor development

Cranial MRI(+)

1

ATM

c.3576G>A

3 years

M

Gait disturbance

3 years

Ataxia, dysmetria

-

-

Prominent cerebellar folia

2

ATM

c.3576G>A

7 years

M

Gait disturbance, frequent fall

3–4 years

Ataxia, dysmetria, tremor, dysarthria

-

DD

Cerebellar atrophy

3

ATM

c.3576G>A

11 years

M

Gait disturbance speech impairment, tremor

3 years

Ataxia, dysmetria, tremor, dysarthria

Frequent febrile convulsion

-

n/a

4

SACS

c.6599A>T

10 years

F

Tremor

n/a

Ataxia, tremor, dysmetria, dysarthria

Hyporeactive deep tendon reflexes

DD

Diffuse cerebellar atrophy

5

SACS

c.7205_7206delTT

4 years 10 months

M

Delayed walking, speech impairment, gait disturbance, frequent fall

12 months

Ataxia, dysarthria

Distal muscle weakness, absent ankle reflexes

DD

Atrophy of the cerebellar vermis

6

SACS

c.7205_7206delTT

13 months

M

Delayed walking

12 months

-

Axial hypotonia, spasticity on lower limbs

DD

n/a

7

COQ8A

c.1396delG

9 years 5 months

M

Gait disturbance

5 years

Ataxia, dysmetria, tremor, dysarthria

Hyperactivity, aggressive behavior

ID

Cerebellar atrophy

DD delayed development, ID intellectual disability, n/a not available “-” represents none

(+)Depicted in Fig. 2

Fig. 2

Cranial magnetic resonance imaging of selected cases. a, b Prominent cerebellar folia on midsagittal and axial MRI section of case 1 (3-year-old male, ATM c.3576G>A homozygous variant). c Cerebellar atrophy on midsagittal MRI section of case 2 (7-year-old male, ATM c.3576G>A homozygous variant). d Midsagittal MRI section of case 4 (10-year-old female, SACS c.6599A>T homozygous variant) exhibits diffuse cerebellar atrophy. e Case 5 (5-year-old male, SACS c.7205_7206delTT homozygous variant) with atrophy of the cerebellar vermis on midsagittal MRI. f Case 7 (9.5-year-old male, COQ8A c.1396delG homozygous variant) with cerebellar atrophy

Discussion

Friedreich’s ataxia (FA) and AT were previously reported to be the two most frequent forms of recessively inherited ataxias [6, 17]. However, those studies were conducted on patients affected with AR progressive cerebellar ataxias onset before the age of 60 in Europe. The current study was mainly designed to research childhood-onset recessive ataxias, and the method of the study is not aimed at including trinucleotide repeat disorders.

The diagnostic rate, using hereditary ataxia NGS panel containing 13 most common ARA genes, was 82.5% (33 out of 40 families). According to a study conducted in France, a molecular diagnosis was made in 27/145 patients with age of onset ranged from 1 to 47 (19%) with mutations in ARA genes [18]. This genetic analysis identified two pathogenic mutations in ANO10 (6 patients), in SETX (4), in SYNE1 and COQ8A (3 each), in SACS and APTX (2 each), and in TTPA, CYP27A1, and POLG (1 each). Recently, a molecular diagnosis was confirmed in 21 (25%) of 84 patients as a consequence of a panel sequencing directed toward ataxia-related genes, in a study from Turkey [19]. Although the panel contains other ARA genes related to neurodegenerative diseases or complex diseases which ataxia is a secondary or late symptom, the study has not included AT. We attributed the significantly high diagnostic rate in our study to the fact that the referred patients met the clinical criteria for this panel, and the NGS panel we used contains the ATM gene as well. Furthermore, advanced diagnostic methods such as larger gene panels covering up to 90–120 ataxia genes or whole-exome sequencing covering all coding regions (yet partly at a variable coverage) can provide genetic diagnosis in unexplained ataxia patients [20, 21, 22]. AT is a rare AR neurodegenerative disease caused by mutations in the ATM gene characterized by progressive neurological dysfunction in association with multisystem abnormalities and cancer predisposition. After the genotype was identified, it became evident that there was a wide spectrum of phenotypic manifestations, including the classical phenotype with mild and severe forms and childhood and adult onset, as well as atypical clinical presentations without oculocutaneous telangiectasia [3]. The molecular genetic analysis results did not show heterogeneous distribution in the region in question (Southeastern Turkey). AT was the most frequently detected ARA with 72.72%, whereas c.3576G>A (p.K1192=) in the ATM gene was the most common homozygous pathogenic variant (33.33%).

The c.3576G>A variant has been first identified in a Turkish AT patient [5]. Furthermore, in a founder effect study, the origin of this mutation was also detected to be in Italians [7]. This mutation, which eliminates the GT consensus dinucleotide at the beginning of intron 26, abolishes this splice site completely and leads to an ATM null allele. The splicing mutation 3576G>A seems to be a leaky mutation that leaves a residual amount of normally spliced ATM transcript [6]. Few patients with milder manifestations of the clinical or cellular characteristics of the disease have been reported. Unlike classical AT patients, these patients exhibited 1–17% of the normal level of ATM. 3576G>A mutation is associated with early-onset slowly progressive ataxia in the literature, and no telangiectasia has been reported [5, 6, 7]. Similarly, the patients in our study also exhibited a mild phenotype of AT clinic without telangiectasia with onset around 3 years of age. Immunodeficiency did not accompany these patients.

In a multicenter study from Turkey including 91 AT patients, genetic mutations were studied only in seven patients, all of whom had biallelic mutations in the ATM gene: c.27delT in two, c.4973del in one, c.20+1G>A in two, c.3576G>A in one, and c.6047A>G/c.887ins in one patient. However, the genotype-phenotype correlation of those patients was not mentioned [23]. Suspitsin et al. [24] identified three pathogenic ATM recurrent mutations (c.5932G>T, c.450_453delTTCT, and c.1564_1565delGA) in 17 out of 30 (57%) patients of Slavic origin. In another AT study, of which the majority of patients were Dutch, the mutation spectrum was heterogeneous. On the other hand, two Turkish families which were included in the mentioned study had c.3576G>A mutation. Likewise, in a third study which was conducted with Chinese patients, the ATM mutation spectrum was found to be heterogeneous [25].

Charlevoix-Saguenay-type spastic ataxia (ARSACS) is characterized by progressive spinocerebellar ataxia, upper motor neuron dysfunction with spasticity, and peripheral neuropathy. This type of ARA is caused by homozygous or compound heterozygous mutation in the SACS gene encoding the sacsin protein. This disorder, considered to be rare, was first described in the late seventies among French Canadians in the isolated Charlevoix-Saguenay region of Quebec [21]. They suggested that it was due to the result of a founder effect. Then, up to 2007, at least 28 mutations have been found in Quebec and non-Quebec patients including ones in Italy, Japan, Spain, Tunisia, and Turkey [22]. Withal, 37% rate of mutations identified in a cohort of Dutch patients suggests that ARSACS is substantially more frequent than previously estimated [26]. Nowadays, it is known that the disorder is not only limited to Quebec region but also occurs worldwide.

The pathogenic SACS gene variants were the second most commonly identified (12.12%) following the ATM gene in our study. These patients had DD and progressive ataxia with extracerebellar findings before the onset of age of 3. Although the core clinical feature of ARSACS is sensory and motor neuropathy, the chief complaints of the current ARSACS cases also included tremor, delayed walking, speech impairment, and unstable gait. Deep tendon reflexes were absent but there were no signs of pes cavus and prominent muscular hypotonia. Electroneurophysiological studies could not have been performed due to the patients’ non-compliance. The novel c.7205_7206delTT (p.L2402Rfs*6) homozygous pathogenic variant in the SACS gene was detected in two siblings from the same family. This sequence change deletes two nucleotides from exon 10 of the SACS (c.7205_7206delTT), causing a frameshift at codon 2402, which creates a premature translational stop signal in the last exon of the SACS mRNA. While this is not anticipated to result in nonsense-mediated decay, it is expected to disrupt the last 2178 amino acids of the SACS protein. This variant is present in population databases (rs773182375, ExAC 0.006%) but has not been reported in the literature in individuals with a SACS-related disease. A 13-month-old male patient with the aforementioned mutation had axial hypotonia and spasticity on lower limbs. He was not able to sit without a support. His 5-year-old brother had ataxic gait and dysarthria. There was no spasticity on lower limbs and the deep tendon reflexes were absent. Atrophy of the cerebellar vermis was detected on cranial MRI.

Primary coenzyme Q10 deficiency-4, also known as AR spinocerebellar ataxia-9, is caused by homozygous or compound heterozygous mutation in the COQ8A (ADCK3) gene and characterized by childhood-onset of cerebellar ataxia and exercise intolerance. Some affected individuals develop seizures and have mild mental impairment. Gene locus was first identified by Mollet et al. in 2008 [27]. They identified various missense or frameshift COQ8A mutations in four ubiquinone-deficient patients from three unrelated families. These patients were considered to be respiratory chain–deficient because they presented a progressive neurological disorder with cerebellar atrophy, DD, and hyperlactatemia. Isolated cerebellar ataxia/atrophy not associated with hyperlactatemia has also been reported [26]. It was then revealed that the patients with primary Q10 deficiency due to COQ8A mutations could demonstrate a wide spectrum of clinical presentations [28].

The homozygous c.1396delG (E466Rfs*11) pathogenic variant in COQ8A gene was identified in three of 34 families (9.09%). This frameshift variant was scanned at the ClinVar database by Shahid Beheshti University of Medical Sciences in Iran in 2017. However, no clinical features were noted. All patients with 1396delG variant in our study had slowly progressive ataxia, cerebellar atrophy, and ID.

Ataxia-oculomotor apraxia syndrome is an early-onset AR cerebellar ataxia characterized by peripheral axonal neuropathy, oculomotor apraxia (defined as the limitation of ocular movements on command), and hypoalbuminemia. Date et al. [29] identified aprataxin (APTX) gene locus in 2001 via genomic mapping of seven families from various regions in Japan. Their clinical presentations were early age of onset (onset in the first or second decade), progressive ataxia, absence of tendon reflexes, distal loss of sense of position and vibration, pyramidal weakness of the legs, and hypoalbuminemia. Cerebellar atrophy was present in all cases, while hematological findings, such as hypoalbuminemia and hypercholesterolemia, became evident during late disease stages [30]. In our study, c.689T>G (p.V230G) homozygous pathogenic variant in the APTX gene was identified in 13- and 17-year-old patients from unrelated families (6.06%), which had not been reported previously. They were admitted with a complaint of ataxic gait, which manifested after puberty. According to our knowledge, this novel variant could be associated with juvenile-onset ataxia.

Conclusion

According to 2018 Turkey Classification of Statistical Region Units, Level 1, the region with the highest percentage (42.6%) of consanguineous marriages was the Southeastern Anatolia (Gaziantep, Adıyaman, Kilis, Şanlıurfa, Diyarbakır, Mardin, Batman, Şırnak, Siirt). This cross-sectional study from Southeast Anatolia includes patients with the ethnic origins of Turkish, Kurdish, and Arabic. Though the patients were analyzed in a highly specialized and crucial center in the Southeast Anatolia of Turkey, they may not necessarily represent the whole population of Turkey which shows diverse and heterogeneous characteristics. Therefore, further multicenter collaborative studies need to be conducted in order to reveal the actual frequency of childhood-onset ataxia in general population.

The most common types of ARAs in this region are AT and ARSACS. ATM gene analysis should be performed foremost on children (even if their parents do not report a consanguineous marriage and come from different nearby towns) presenting early-onset ataxia from Southeastern Anatolia. If there is a concomitant peripheral neuron involvement, SACS gene analysis should be preferred. This valuable data will be a guide for the first step molecular diagnostic approach before requesting the NGS panel.

Notes

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pediatric GeneticsCengiz Gökcek Maternity & Children’s HospitalGaziantepTurkey
  2. 2.Department of Medical GeneticsErsin Arslan Education and Research HospitalGaziantepTurkey
  3. 3.Department of Pediatric NeurologyCengiz Gökcek Maternity & Children’s HospitalGaziantepTurkey

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