Chromosome 1p36 Deletion Syndrome: Four Patients with Variable Presentations

Abstract

Chromosome 1p36 deletion accounts for around 1% of cases of intellectual disability. The pattern of clinical features includes developmental delay, hypotonia, seizures, short stature, intellectual disability, vision and hearing deficits, congenital heart disease, and renal abnormalities. The size of deletion can be variable. We report four cases of 1p36 deletion syndrome detected in the past 3 years in a genetic clinic. One patient was detected by next-generation sequencing, another by chromosomal microarray, and the remaining two by multiplex ligation-dependent probe amplification. We discuss the variable presentations in the four children. Early diagnosis enables better prognostication and further reproductive planning.

Introduction

Chromosome 1p36 deletion syndrome (OMIM #6078720) is considered a common subtelomeric microdeletion found in children, with an incidence of 1 in 5,000 to 1–10,000 individuals. ^{1 2} Distinctive craniofacial features include microbrachycephaly, prominent forehead, deep-set eyes, straight eyebrows, broad/flat nasal bridge, and midface hypoplasia, described both in earliest reported cases, as in large cohorts of individuals with 1p36 deletion syndrome. ³ Most of the patients with this chromosomal deletion have larger terminal deletions, or heterozygous deletion of the distal chromosomal band on the short arm of chromosome 1, whereas other rearrangements involving interstitial deletions or more complex rearrangements are less commonly seen. ^{4 5} Several chromosomal deletion syndromes such as Prader–Willi, Angelman, or Williams, have uniformly sized deletions lead to typical phenotypic presentations. ⁶ Contrarily, chromosome 1p36 deletion syndrome patients display variable-sized deletions and diverse phenotypic manifestations. ⁷ This phenotypic variability may be due to the effect of contiguous gene loss, or imprinted genes related to the parental origin of the deletion, and many chromosome 1p36-related phenotypes may arise from haploinsufficiency for more than one gene within a specific genomic region. ⁸

Patients and Methods

Four unrelated Indian children with seizures and developmental delay were identified as having 1p36 deletion syndrome. The four children were sporadic cases, one was boy and three were girls aged between 5 months and 2 years. Written informed consent for publication of case report and accompanying images were obtained from the guardians of all patients. The clinical findings, dysmorphic features, and the investigations of other organ functions such as the endocrine glands, brain, and heart were also included, along with growth and developmental details.

Blood samples were collected from patients and their parents with appropriate informed consent. The genomic DNA was extracted from peripheral blood leukocytes using the DNA extraction kits (Qiagen Inc., The Netherlands). Clinical diagnosis of 1p36 deletion syndrome was established in three patients by targeted multiplex ligation-dependent probe amplification (MLPA) using the SALSA MLPA probemix P245-B1-Microdeletion syndrome-1A (MRC Holland). MLPA kit P245-B1 having 50 different MLPA probes with amplification products corresponding to the GABRD , TNFRSF4 , and GNB1 genes located at the 1p36.33 region. Polymerase chain reaction–amplified products were separated using ABI 3500 Genetic Analyzer (Applied Biosystems, Foster City, California, United States) and raw data were analyzed by Coffalyser.Net software (MRC Holland). Next-generation sequencing (NGS) was done in two patients as per standard protocols. In one patient, chromosomal microarray (CMA) was done following initial NGS testing using Illumina single nucleotide polymorphism array. NGS was performed on Illumina platform covering for possible target genes using a capture system as per the manufacturer's standard protocols. The libraries were sequenced to mean >80 to 100X coverage. BWA aligner was used to align the obtained sequences to the human reference genome (GRCh37/hg19). Recalibration of base quality and realignment of reads based on indels were analyzed. The significance of variants was identified through standard bioinformatic pipelines. Clinically significant variants were filtered based on allele frequency in gnomAD, dbSNP, ExAC, 1000 Japanese Genome, and our Indian population reference databases. Nonsynonymous and splice site variants were used for clinical interpretation.

Results

Case 1

A 4-year-old boy, born to first pregnancy of nonconsanguineous parents, was referred with a complaints of global development delay and abnormal body movements since early infancy. He had its first seizure at 4 months, which was focal involving the right lower and upper limb. He had persistent seizures over a period of 2 months during which a seizures changed to generalized tonic-clonic type. They were gradually controlled after 1 year of age. He was born at term by cesarean section due to meconium-stained amniotic fluid, presenting delayed cry at birth, although without requiring hospitalization. Birth weight was 1,750 g. He recognized his parent's faces at 1 year of age, and attained neck control at 2 years of age. On examination at 4 years of age, he could sit only with support. His weight, height, and head circumference corresponded to −2.7, −3, and −3.16 Z-scores, respectively. He had a hypotonic face with gestalt suggestive of brachycephaly, straight eyebrows, deep-set eyes, wide and depressed nasal bridge, midface retrusion, and pointed chin ( Fig. 1A ), and cortical thumb sign and hemangioma over left ankle were also observed. He had decreased hearing and vision. His cardiac evaluation by echocardiography was normal. MLPA testing showed a haploinsufficiency of TNFRSF4 , GABRD , and GNB1 genes, indicative of heterozygous deletion at 1p36 chromosomal region ( Fig. 2 ). Karyotype of the parents was advised and found no breaks, or translocation involving 1p36 region. Highlight was that seizures resolved spontaneously.

Fig. 1.

( A ) Patient 1 with hypotonic face, straight eyebrows, deep-set eyes, wide and depressed nasal bridge, midface retrusion, and pointed chin. ( B ) Patient 2 showing deep-set eyes, hypertelorism, blue sclera, and straight downslanting eyebrows. ( C ) Patient 3 with long face, medial flare of eyebrows, straight downslant of eyebrows, strabismus, downslanting palpebral fissures, epicanthic folds, prominent philtrum (i) at 1.5 years of age, and coarse facies, low-set ears at 3.5 -years of age (ii). ( D ) Patient 4 with a round face, straight eyebrows, prominent philtrum, and blue sclera.

Fig. 2.

Multiplex ligation-dependent probe amplification ratio chart of patient 1 using kit P245-B1 showing heterozygous deletion of all three probes for chromosome band 1p36.33.

Case 2

An 18-month-old girl was referred to pediatric emergency with respiratory distress fever, cough, and cold. She was managed for acute bronchiolitis. She was the product of the second pregnancy of nonconsanguineous parents. The mother had cervical lymphadenopathy in the third trimester, and fine needle aspiration cytology showed acid-fast bacilli positivity. She was born at term by cesarean section as there was a cord around the neck. Postnatal period was uneventful. She had four hospital admissions due to respiratory distress, and received a blood transfusion for anemia in one of them. She achieved neck control at 10 months and sat with support at 1 year. She spoke bisyllables at 1 year. At 18 months, she was anxious around strangers, interacted with parents, and shook hands. On examination, hypotonia was present. Weight, height, and head circumference corresponded to −3.36, −2.53, and −2.05 Z-scores, respectively. She had dysmorphic facial features including brachycephaly, deep-set eyes, hypertelorism, straight eyebrows, and short tapering fingers ( Fig. 1B ). Respiratory distress resolved after humidified oxygen support, but persistent hepatosplenomegaly was noted. Liver was 7 cm and spleen more than 6 cm below costal margins, respectively. Serology for TORCH infections was negative. Abdomen ultrasonography detected a 2 × 2.5 mm cyst in the V-segment of liver. Magnetic resonance imaging (MRI) of the brain was suggestive of right transverse and sigmoid sinus thrombosis. She had first seizures at 6 months of age which were generalized tonic-clonic. MLPA testing showed deletion of the TNFRSF4 gene, indicative of heterozygous deletion in chromosome1p36 region. Highlight in this case was recurrent respiratory infections and pneumonias.

Case 3

A 10-month-old girl was presented with seizures and developmental delay. On examination, she had coarse facies, microcephaly, long face with prominent chin, deep-set eyes, medial flare of eyebrows, straight eyebrows, downslanting palpebral fissures, epicanthic folds, prominent philtrum, low-set and anteverted ears ( Fig. 1C ). CMA demonstrated an 8.5-Mb heterozygous deletion (Chr1:1099840-9664754) at 1p36.33-1p36.22 ( Fig. 3 ). The couple was counseled regarding problems and reproductive options. The MLPA done later also confirmed deletion at 1p36 region. The prenatal diagnosis as well as segregation analysis in parents was done in subsequent pregnancy by two techniques—CMA and MLPA, and the fetus and parents were found to be unaffected.

Fig. 3.

Chromosomal microarray in patient 4 using an Illumina single nucleotide polymorphism array demonstrated an 8.5-Mb heterozygous deletion within 1p36.33-p36.22. The black arrows show the deleted region in the chromosome 1. Genes in the deleted region include AGRN , TNFRSF4 , B3GALT6 , GABRD , SKI , PEX10 , PRDM16 , TP73 , NPHP4 , PLEKHG5 , CAMTA1 , and ESPN .

Case 4

A 1-year-old girl was referred with developmental delay and history of neonatal hypoglycemia. Her birth weight was 2,340 g. She required double volume exchange transfusion was done for neonatal hyperbilirubinemia. There was no history of seizures. She had speech delay, mild facial dysmorphism ( Fig. 1D ), squint, and lower limb hypertonia. Her head circumference was normal. The MRI of the brain showed pachygyria and pontine hypoplasia. NGS-based assay was done to look for copy number variations (CNVs) and single nucleotide variants. A heterozygous variants in LRPPRC , ARHGAP31 , SCN8A , and SPTAN1 genes was found, and also, a small deletion of 340.343 kb on chromosome 1p36.33 region. Heterozygous variants of unknown significance were also tested in her parents by Sanger sequencing and found to be not related to the phenotype. Highlight in this case was the presence of pontine hypoplasia.

Discussion

Four patients with chromosome 1p36 deletion have been diagnosed using cytogenetic and molecular techniques. Observed deletions in our cases were de novo and do not seem to include other chromosomal segmental imbalances. In the present case series, three patients had an apparent classical presentation of a severe 1p36 deletion syndrome. Patient 4 had a relatively milder clinical phenotype. All studied patients had the characteristic facial features, and two of them, seizures. Thus, the severity of phenotype depends on the extent of deletion size, which can be used to explain the clinical variability among patients. ⁹ However, patients with a deletion of different sizes have been found to manifest similar phenotypes. ¹⁰ Patients having smallest deletion (199 kb) has been reported with phenotypic manifestations such as hypotonia, developmental delay, intellectual disabilities, pointed chin, straight eyebrows, and short palpebral fissures. ¹¹ Instead, the patient showing the largest chromosomal loss (30 Mb) presented deep-set eyes, delayed growth, cardiac and cerebral anomalies. Previous reports in the medical literature have reported that 1p36-related phenotypes may arise from haploinsufficiency for more than one gene within a specific genomic region. ¹² Some of the strongly associated 1p36 genes including their function and possibly associated phenotypes with haploinsufficiency are listed in Table 1 . In reported publications, evidence implicating haploinsufficiency of some of the strongly implicated genes based on the pattern of expression or deleterious variations found in these genes presumed functions of these genes or from the same phenotypes seen in some animal models including mouse and zebrafish. ¹³

Table 1. Summary of genes and their functions with possible contribution to 1p36 deletion syndrome phenotypes.

Gene	Functions	Phenotypes possibly associated with haploinsufficiency
MMP23B	Involved in bone matrix resorption and bone remodeling	Large, late-closing anterior fontanel
GABRD	It mediates the synaptic inhibition of neuronal excitability in the mammalian brain	Neurodevelopmental abnormalities, neuropsychiatric problems, seizures
SKI	It functions as a negative regulator of the TGF-β signaling	Developmental delay, intellectual disability, seizures, orofacial clefting, congenital heart defects
PRDM16	It regulates leukemogenesis palatogenesis, neurogenesis, and brown fat development	Left ventricular noncompaction, dilated cardiomyopathy
KCNAB2	Neurotransmitter release, heart rate smooth muscle contraction	Developmental delay, intellectual disability, seizures
RERE	Nuclear receptor coregulation that positively regulates retinoic acid signaling	Short stature, developmental delay, intellectual disability, brain anomalies, vision problems, hearing loss, renal anomalies, congenital heart defects, cardiomyopathy
CASZ1	Zinc finger transcription factor, act as tumor suppressor	Congenital heart defects and cardiomyopathy
PDPN	Integral membrane glycoprotein. The specific function has not been determined but it has been proposed as a marker of lung injury	Congenital heart defects and cardiomyopathy
ATAD3A	Protein degradation, membrane fusion, microtubule severing	Neonatal hypotonia, cardiomyopathy, and respiratory insufficiency
ECE1	Involved in proteolytic processing of endothelin precursors to biologically active peptides	Congenital heart defects
HSPG2	Transcription coregulator	Cleft palate, congenital heart defects
LUZP1	Exact function not known in Homo sapiens . In mice, LUZP1 gene affects neural tube closure	Congenital heart defects, cleft palate
SPEN	Transcriptional repressor	Congenital heart defects, cardiomyopathy, short stature, neurodevelopmental phenotypes

Genotype–phenotype correlation in monosomy 1p36 syndrome remains widely subtle due to the clinical heterogeneity of these patients. Dominant dysmorphic features include deep-set eyes, straight eyebrows, prominent philtrum, and late closing anterior fontanelles. The variable expressivity and reduced penetrance can also be due to other genetic or epigenetic factors. Deletions in the GABRD , the human gamma-aminobutyric acid A receptor delta subunit gene, or in the proto-oncogene SKI , or in KCNAB2 , a voltage-gated potassium channel β-subunit gene, can be related to the susceptibility to generalized seizures, developmental delay, and intellectual disabilities. ¹⁴ Homozygous deletions of ATAD3A gene in 1p36.33 region are associated with a severe phenotype with neonatal hypotonia, respiratory insufficiency, and pontocerebellar hypoplasia. ¹⁵ Also, 1p36.33 duplication has been also associated with a severe phenotype with neonatal hypotonia, cardiomyopathy, and respiratory insufficiency. It is said that abnormalities result from abnormal cholesterol and mitochondrial metabolism. More studies are needed on the ATAD3A gene and nearby genes and related phenotypes. In patient 4, deleted region included GABRD and CAMTA1 genes. GABRD variants are associated with epileptic encephalopathy, and CAMTA1 is associated with delayed psychomotor development, hypotonia, nonprogressive ataxia, and strabismus. Possibly, CAMTA1 heterozygous deletion was majorly responsible for the relatively milder phenotype with pontocerebellar hypoplasia. At least 11 types of pontocerebellar hypoplasia have been described with multiple implicated genes. ¹⁶

Most chromosome1p36 deletions are reported to be maternally derived. In prenatally detected severe cases on antenatal sonography, cardiac defects, especially Ebstein anomaly, are suggestive along with prenatal growth retardation.

Chromosome 1p36 deletion being a microdeletion syndrome, both conventional and molecular cytogenetic techniques can be employed to identify the deletion. Standard cytogenetics techniques such as karyotyping and fluorescence in situ hybridization can identify the deletion in 50 to 60% of the patients, but are of limited use nowadays due to poor resolution. MLPA and array-based CNV analysis are the existing gold standard methods for detection of disease-causing CNVs and can identify up to 95% deletions and duplications. ¹⁷ Moreover, further studies can provide vital supportive confirmation for the contribution of these genes and role of the genes in the 1p36 region involved in manifestations of certain characteristics of the phenotype.

To summarize, chromosome 1p36 deletion is a relatively common microdeletion syndrome. Craniofacial features such as straight eyebrows, deep-set eyes, and late closing anterior fontanelles play an important role in clinical diagnosis. Seizures are very commonly seen in this disorder (70–75%) among affected individuals. Risk of recurrence is lower in case of de novo findings; however, genetic counseling and antenatal diagnosis are the standard of care. Prenatal diagnosis can be offered on chorionic villus samples at 12 to 14 weeks of gestation through MLPA or CMA. Hence, early diagnosis enables better prognostication and further reproductive planning in the family.

Conclusion

Chromosome 1p36 deletion syndrome is one of the commonest clinically recognized malformation syndromes. Three of four patients in present series had seizures in infancy. Early diagnosis has substantial implications for the affected patients and their family. Further characterization of smaller deletions in the chromosome1p36 region is warranted. Newer techniques in CNV identification enable appropriate genetic counseling.

Established Facts and Novel Insights

Established Facts

1. Chromosome 1p36 deletion syndrome is a common microdeletion syndrome.

2. Deletion sizes are variable.

Novel Insights

1. Seizures are a common manifestation.

2. Pachygyria and pontine hypoplasia can be seen even in small deletions depending on genes in deletion region.

Funding Statement

Funding None.