Clinical characteristics and long-term follow-up of twin boys with de novo interstitial 1q25.2q25.3 deletion and 4q35.2 microduplication

doi:10.21203/rs.3.rs-4842964/v1

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Case Report

Clinical characteristics and long-term follow-up of twin boys with de novo interstitial 1q25.2q25.3 deletion and 4q35.2 microduplication

https://doi.org/10.21203/rs.3.rs-4842964/v1

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Background：Growth hormone deficiency (GHD) is the most prevalent form of pituitary hormone insufficiency.Genetic factors are increasingly recognized to play a significant role in the etiology of GHD.Deletions involving the long arm of chromosome 1 are rare, with only approximately 40 reported cases featuring detailed molecular characterization of deletion size and merely four instances involving deletions within region 1q25. and no related treatment has been reported

Case presentation：The identical twin boys were evaluated at the pediatric endocrinology clinic of Tongji Hospital due to a prolonged history (over 5 years) of short stature and cognitive delays. Upon diagnosis of GHD, hematuria, and intellectual disability, genome-wide CNV analysis revealed deletions at 1q25.2q25.3 and microduplications at 4q35.2 involving genes such as LHX4 and FAT1. These overlapping genomic alterations spanned 6.557 Mb and 141 Kb in these regions respectively, aligning with their clinical phenotypes.Furthermore, comprehensive exomic screening of 97 glomerular disease-associated genes showed no variations. Following diagnosis, the twins underwent over three years of rhGH therapy which led to significant catch-up growth and increased levels of IGF-1 and IGFBP3 without any adverse endocrine reactions or exacerbation of renal pathology.

Conclusions：This investigation delineates a novel syndromic manifestation in twin boys characterized by GHD, thin basement membrane nephropathy (TBMN),and intellectual disability associated with specific genetic alterations at 1q25.2-q25.3 and 4q35.2.The treatment with rhGH over an extended period was efficacious in promoting growth without discernible adverse effects underscoring its safety & effectiveness in this unique context.

Growth hormone deficiency

twin boys

deletion

1q25

recombinant human growth hormone

Growth hormone deficiency (GHD) is the most common pituitary hormone deficiency. It can be isolated or in combined with the deficiencies of other pituitary hormones. Although the majority of the cases are idiopathic, genetic factors are increasingly recognized to have an important role in the etiology of growth hormone deficiency(1). More rarely, chromosomal abnormalities have also been reported to be associated with it, such as Prada-Willi syndrome, Cat-Eye syndrome, Jacobsen syndrome and Chromosome 1q deletion(2–4). Here we report the responses of long-term treatment of growth hormone in twin boys with a de novo heterozygous deletion of 1q25.2-25.3 and microduplication of 4q35.2, recognized by growth hormone deficiency, hematuria, and intellectual disability.

Patients

At the baseline, blood cell count, liver and kidney functions, urinary routine test, thyroid hormones, fasting blood glucose, adrenal functions, sex hormones were accessed. Growth hormone (GH) stimulation test was conducted with clonidine (0.004mg/kg orally) and insulin (0.075IU/kg intravenously). Blood was withdrawn at times 0, 30, 60, 90 min for GH concentrations. During the treatment of recombinant human growth hormone (rh-GH), patients were visited every 3–4 months. At each visit, height and weight were monitored. Thyroid hormones, fasting blood glucose, insulin, and urinary routine were tested at each visit. Adrenal function and renal ultrasonography were monitored annually.

The protocol was approved by the Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, and conducted in accordance with the Declaration of Helsinki (TJ-IRB20201016). Informed consent was obtained in writing from the parents, and child assent was obtained as age-appropriate.

Copy number variation (CNV) analysis

With the consent of the patients and their parents, venous blood samples were obtained from them. Genomic DNA was extracted from each sample and whole genome deep sequencing was performed (MyGenostics, Beijing). After quality control, the reads were mapped to the UCSC hg19 human reference genome using BWA software, and duplicated reads were removed by GATK MarkDuplicates. After two-step bias correction of mapped read, the binary segmentation algorithm was used to identify the candidate CNV regions and determine CNV genotype. U-test and Parallelism-test was used to estimate the genotype and the significance of each segment(5, 6).

Exome sequencing of genes associated with glomerular disease

The DNA librariy was prepared by DNA sample prep reagent set (MyGenostics, Beijing). Exons of 97 genes known to be associated with glomerular disease (Table 1) were captured using GenCap WES capture kit (MyGenostics, Beijing) and deep sequenced on the Illumina HiSeq X ten platform (Illumina, California)(7). Variants were identified by GATK and annotated with ANNOVAR, and were further associated with multiple databases, such as,1000 Genomes, ESP6500, dbSNP, EXAC, Inhouse (MyGenostics), HGMD, and predicted by SIFT, PolyPhen-2, MutationTaster, GERP++. Sanger sequencing was performed to confirm the potentially pathogenic variants. The identified variant was classified according to the American College of Medical Genetics (ACMG) criteria(8).

Table 1

Analysis gene list of glomerular disease
ABCB1	ACTN4	ALG1	ALG13	ANLN	APOA1	APOE	APOL1
APTX	ARHGAP24	ARHGDIA	B2M	BDNF	BRAF	CD151	CD2AP
CD44	CFB	CFH	CFHR1	CFHR3	CFHR5	CF1	COL4A3
COL4A4	COL4A5	COL4A6	COQ2	COQ4	COQ6	COQ7	COQ8A
COQ8D	COQ9	CRB2	CUBN	DGKE	EMP2	EPAS1	FAT1
FGA	FLG	FN1	GC	GLA	GSN	INF2	ITGA3
ITGB4	KANK1	KANK2	KANK4	LAMB2	LAMB3	LAMC2	LMNA
LMX1B	LYZ	MAGI2	MEFV	MIF	MME	MTTL1	MYH9
MYO1E	NEIL1	NEK8	NPHP3	NPHS1	NPHS2	NUP107	NUP205
NUP93	NXF5	PAX2	PAX6	PDSS1	PDSS2	PEX1	PLA2R1
PLCE1	PMM2	PTPRO	SCARB2	SGPL1	SLC17A5	SLC35A2	SMARCAL1
THSD7A	TRPC6	TSC2	TTC21B	UMOD	WDR73	WT1	XPO5
ZMPSTE24

Medical history and Physical examinations

Monozygotic twin boys aged 5 years and 8 months (Case Ⅰ and Case Ⅱ) presented to the pediatric endocrinology clinic of Tongji Hospital because of short stature and mental retardation for more than five years. They began to sit at the age of 7 months, and to walk and speak at the age of two years old. At the time of their first visit, they could only speak sentences with three words and had difficulties in communication.

Their parents were non-consanguineous and apparently normal. The father’s and mother’s height were 173 cm and 163 cm, respectively. The patients were born by cesarean section at the gestational age of 32 weeks because of premature rupture of fetal membranes. Their conditions were generally normal at birth, with no apnea or birth injury. The birth weights of Case Ⅰ and Case Ⅱ were 2.4 kg (90ཞ95th percentile) and 2.3 kg (50ཞ90th percentile), respectively. Both of them had cryptorchidism, which was corrected by surgery at the age of five years old.

Physical examinations showed sever growth retardation, and their heights were 91.0 cm (Case Ⅰ, -5.27 SDS) and 90.5 cm (Case Ⅱ, -5.38 SDS). The weights of Case Ⅰ and Case Ⅱ were 12 kg (< 3rd percentile) and 11 kg (< 3rd percentile) respectively. Each of them had a single transverse palmar crease. Hypertelorism Bulbous nose.Sparse eyebrow.Abnormal palate.Micro/retrognathia and Short/broad neck

No abnormalities in facial features, limbs or vertebrates were observed in them. Systolic murmurs of grade II/VI were heard on the precordium of both Case Ⅰ and Case Ⅱ. They had no enlargement of the livers and spleens. Their testicular volumes were 1ml at the first visit.

Laboratory Investigations

Their laboratory tests showed normal blood cell counts, normal liver and kidney functions, normal electrolytes levels, normal blood gas values, normal glucose and insulin levels, normal blood lipid levels. Their adrenocortical functions and thyroid functions were also normal (data not shown). Their growth hormone stimulation tests showed impaired growth hormone secretion with the peak values of 1.08 ng/ml (Case Ⅰ) and 0.60 ng/ml (Case Ⅱ). Both of them had significantly decreased Insulin-like growth factor 1 (IGF-1) and Insulin-like growth factor-binding protein 3 (IGFBP-3) levels.

The pituitary magnetic resonance imaging (MRI) of both the twins showed hypoplastic pituitary glands, with the absence of lower pituitary stalks and an ectopic posterior pituitary, which consistent with pituitary stalk interruption syndrome (PSIS) (Fig. 1). The echocardiogram of Case Ⅰ showed a bicuspid aortic valve (BAV) and aortic insufficiency, while only a BAV was found in the echocardiogram of Case Ⅱ. No abnormalities were observed in their electrocardiograms.

Their routine urinalyses showed 3 + occult blood without protein. 60–70 red blood cells (RBCs) per high-power field were found in their microscopic urinalyses, with more than one third of dysmorphic RBCs, suggesting glomerular hematuria. Further urinalyses showed normal levels of albumin/creatinine, calcium/creatinine, N-acetyl-beta-d-glucosaminidase (NAG), β-2 microglobulin (β-2 MG), retinol-binding protein (RBP), neutrophil gelatinase-associated lipocalin (NGAL), and in their urine. No abnormalities were detected in their kidney ultrasound. Both of the twins underwent renal biopsy. Light microscopy of their kidney biopsy specimens revealed a pattern of mild mesangial proliferation with interstitial lesion.Immunofluorescence microscopy disclosed no deposit of IgA, IgG or C3. Electron microscopy showed thinning of glomerular basement membrane (GBM).

Genetic Analysis

A 6.56 Mb heterozygous deletion of 1q25.2-25.3, a 280 bp duplication of 2q31.2, a 161 bp duplication of 4q35., a 152 bp duplication of 6p12.1, a 105 bp duplication of 8q21.11, and a 245 bp duplication of 23q21.31q21.32 were identified in Case Ⅰ (Table 2). In Case Ⅱ, a 6.562 Mb heterozygous deletion of 1q25.2-25, a 114 bp deletion of 4p14, and a 146 bp duplication of 4q35.2 were identified (Table 3). None of the CNVs mentioned above were found in their apparently healthy parents, Chromosome Polymorphism Database, or Decipher database. Moreover, no variations were detected in the exomes of 97 genes known to be associated with glomerular disease.

The genes in the overlapping regions overlap in deletions and duplications were listed in Table 4. Among them, 10 genes were included in OMIM database: TSEN1, CACNA1E, NCF2, NPHS2, XPR1, RNASEL, TOR1AIP1, LAMC2, LHX4, GLUL, and FAT1.

Table 2

CNV analysis of Case Ⅰ.
Type	Size (Kb)	Coordinates (hg19)	Genes Involved
Deletion	6560	1q25.2q25.3 (chr1:178953588–185514075) *1	SOAT1; TDRD5; FAM163A; FAM20B; TOR1AIP2; RGSL1; SMG7; NPHS2; LHX4AS1; MIR3121; KIAA1614AS1; LINC01732; LINC01699; LINC01344; LINC00272; LINC01686; LINC01688; LOC647070; LAMC1-AS1; SMG7-AS1; LINC01633; TRMT1L; SWT1; GS1- 279B7.1; CACNA1E; XPR1; RGL1; RGS8; EDEM3; NCF 2; SHCBP1L; AXDND1; LHX4; ACBD6; TSEN15; IVNS1ABP; ABL2; QSOX1; GLUL; TOR1AIP1; STX6; NMNAT2; NPL; MR1; DHX9; APOBEC4; LAMC1; CEP350; T EDDM1; LAMC2; TOR3A; OVAAL; RNF2; NIBAN1; IE R5; ARPC5; KIAA1614; COLGALT2; ZNF648; C1orf21; RGS16; MIR12116; RNASEL
Duplication	280	2q31.2 (chr2:179385257–179665423) *3	TTN; LOC101927055; MIR548N; TTN-AS1;
Duplication	161	4q35.2 (chr4:187499750–187660838) *3	FAT1
Duplication	152	6p12.1 (chr6:56341671–56494506)*3	DST
Duplication	105	8q21.11 (chr8:77863947–77969091) *3	MIR3149; PEX2;
Duplication	245	23q21.31q21.32 (chr23:91624067–91869980) *3	PCDH11X

Underlines indicates the genes included in OMIM database.

Table 3

CNV analysis of Case Ⅱ.
Type	Size (Kb)	Coordinates (hg19)	Genes Involved
Deletion	6562	1q25.2q25.3 (chr1:178948580–185511075) *1	SOAT1; TDRD5; FAM163A; FAM20B; TOR1AIP2; RG SL1; SMG7; NPHS2; LHX4-AS1; MIR3121; KIAA1614- AS1; LINC01732; LINC01699; LINC01344; LINC00272 ; LINC01686; LINC01688; LOC647070; LAMC1-AS1; SMG7-AS1; LINC01633; TRMT1L; SWT1; GS1-279B7.1; CACNA1E; XPR1; RGL1; RGS8; EDEM3; NCF2; SHCBP1L; AXDND1; LHX4; ACBD6; TSEN15; IVNS 1ABP; ABL2; QSOX1; GLUL; TOR1AIP1; STX6; NMNAT2; NPL; MR1; DHX9; APOBEC4; LAMC1; CEP350; TEDDM1; LAMC2; TOR3A; OVAAL; RNF2; NIBAN1; IER5; ARPC5; KIAA1614; COLGALT2; ZNF648; C1orf21; RGS16; MIR12116; RNASEL
Deletion	114	4p14 (chr4:39094829–39208867) *1	WDR19; KLHL5
Duplication	146	4q35.2 (chr4:187494747–187640837) *3	FAT1

Underlines indicates the genes included in OMIM database.

Table 4

Overlap regions of deletions and replications in Case Ⅰ and Ⅱ.
Type	Size (Kb)	Coordinates (hg19)	Genes in overlapping region
Deletion	6557	1q25.2q25.3 (chr1: 178953588–185511075)	TRMT1L, TSEN15, CACNA1E, LAMC1, LINC01732, MR1, NPL, NCF2, SMG7, ABL2, AXDND1, CEP350, FLJ23867, OVAAL, KIAA1614, TEDDM1, SMG7-AS1, RGS8, NPHS2, FAM163A, SOAT1, RGSL1, IVNS1ABP, FAM20B, LINC01699, TOR1AIP2, XPR1, RGL1, RNASEL, DHX9, STX6, SWT1, TOR1AIP1, LHX4-AS1, ARPC5, EDEM3, LAMC2, KIAA1614-AS1, COLGALT2, MIR3121, LHX4, LINC01686, GLUL, ACBD6, C1orf21, LINC01344, TDRD5, IER5, RGS16, APOBEC4, NMNAT2, LINC00272, TOR3A, RNF2, GS1-279B7.1, FAM129A, QSOX1, SHCBP1L, LINC01633, LINC01688, ZNF648
Duplication	141	4q35.2 (chr4: 187499750–187640837)	FAT1

Underlines indicates the genes included in OMIM database.

Treatment and follow-up

They have been followed up for more than 3 years until now, and they were 8 years and 9 months old in the last visit. Both of them were treated with recombinant human growth hormone (rhGH) since the age of 6.5 years old, with the dose of 0.11-0.13U/kg/d. The heights and weights of them were showed in the growth charts (Fig. 2). The testicular volumes of Case Ⅰ and Case Ⅱ were 1–2 ml in the last visit. Their IGF-1 and IGFBP3 levels increased dramatically (Fig. 3). They showed normal liver function, thyroid hormones, glucose levels, and adrenal hormones, which were monitored every 3 months (data no shown). Their routine urinalyses were done every two to three months and the results showed 2 ~ 3 + occult blood with no protein detected. They had normal kidney function (monitored once 3 months) and their annually ultrasonography of the kidneys were normal.

We report a new syndrome in twin boys manifesting as GHD, thin basement membrane nephropathy (TBMN) and intellectual disability, with interstitial 1q25.2q25.3 deletion and microduplication of 4q35.2. They were followed-up and treated with rhGH for more than 3 years. During the treatment, the twins showed significant catch-up growth, with great increase in IGF-1 and IGFBP3. Until the last visit, we found no endocrine side-effects or deterioration of the nephropathy.

Their overlapping regions in deletions and duplications were a 6.557-Mb region at 1q25.2q25.3 and a 141-Kb segment at 4q35.2 respectively. It’s reasonable to associate the phenotypes of the twins with the two CNVs. However, the causative relationships between the phenotypes and CNVs needed to be further discussed.

Deletions of the long arm of chromosome 1 are rare. Based on the location of the deletion of Chromosome 1q, the patients were classified into three groups: proximal (1q21-22→q25), interstitial (1q24-25→q32), and distal (1q42-43→qter) deletion(3). The 6.557-Mb deleted region of our patients located at 1q25.2q25.3, categorized into the interstitial deletion of Chromosome 1q. Up to date, there are only about 40 previously reported cases with molecular characterization of the deletion size(9–13). Among them, majority cases were large deletions encompassing multiple cytogenetic bands. There were about 6 cases reported with deleted regions encompassed 1q25.2q25.3, and only 4 cases with deletions within 1q25(13,14). The deletion regions and phenotypes of these reported patients were summarized in Table 5.

Major abnormalities of interstitial 1q deletions were growth retardation and developmental delay(3,14). Chatron et al. reported patients with growth retardation and intellectual disability. They suggested that a 2.7-Mb region (chr1:178,514,910–181,269,71) in 1q25.2q25.3 was the shortest region of overlap (SRO) responsible for the phenotypic features, and proposed the genes FAM20B and LHX4 may be candidate for the phenotypes(14). Not surprisingly, the vast majority of reported SRO was comprised in the deleted region of our cases, including FAM20B and LHX4 genes.Thus, the 6.557-Mb deletion region in 1q25.2q25.3 could be associate with growth retardation and developmental delay in our patients.

LHX4 is critical in the proliferation and differentiation of pituitary progenitor cells. The haploinsufficiency of LHX4 isassociated withcombined pituitary hormone deficiency, as well as brain abnormalities (PSIS, poorly developed sella turcica, Chiari syndrome, ect.)(15,16). As reported, the phenotypes related with LHX4 mutations are variable from isolated growth hormone deficiency to complete panhypopituitarism(17). In our cases, the twins showed isolated growth hormone deficiency, without the defects in other pituitary hormones throughout the 3-year follow-up. However, corticotrophin deficiency has been observed in at least half of the reported patients with LHX4 mutations, and can occur later in life(17,18). Moreover, the function of pituitary LH/FSH secretion needs to be evaluated later, since the twins in present study were still in prepubertal stage. Therefore, careful follow-up monitoring of the hypothalamic-pituitary-adrenal and gonadal function in the patients will be necessary.

TBMN was another feature of our cases. We reviewed all the entries from the DECIPHER database and the reported cases in publications, with overlapping deletions of 1q25.2q25.3 or duplications at 4q35.2. None of them reported hematuria or nephropathy. We noticed NPHS2, the gene associated with steroid-resistant nephrotic syndrome (SRNS), was included in the deletion region in our cases. To see whether there were compound heterozygous alteration in NPHS2 and to elucidate the cause of TBMN, we conducted additional exon sequencing of the reported genes associated with glomerular disease. Unfortunately, we didn’t find any pathogenic alteration.

Besides the deletion at 1q25.2q25.3, our patients had the 141-Kb microduplication at 4q35.2, including only one gene named FAT atypical cadherin 1 (FAT1). FAT1 is highly expressed in a number of fetal epithelia, facilitates cell to cell adhesion and is likely essential in developmental processes and cell communication(19). It was recognized as putative tumor suppressor or oncogene, and mutations in FAT1 are found in a variety of tumors(20). Recently, recessive loss-of-function mutations in FAT1 were found to cause a distinct renal disease entity in four families with a combination of steroid-resistant nephrotic syndrome, tubular ectasia, and hematuria(21). However, we retrieved far fewer reports of FAT1 or 4q35.2 duplications. Until now, no exactly pathological effects were report about FAT1 duplication. There was only one case presented as isolated posterior urethral valves (Boghossian et al., Subject 6), was found to have similar duplication with our cases, involving both FAT1 and MTNR1A genes(22). However, the phenotype was not consistent with our cases. Thus, the pathogenicity of the 141-Kb microduplication at 4q35.2 still needs further investigations.

In conclusion, we reported a new syndrome in twin boys manifesting as GHD, thin basement membrane nephropathy (TBMN) and intellectual disability, with interstitial 1q25.2q25.3 deletion and microduplication of 4q35.2. The rhGH was beneficial for their growth without obvious side-effects, and careful follow-up will be necessary for the HPA and HPG functions in the patients.

GHD

growth hormone deficiency

CNVs

copy number variations

rhGH

recombinant human growth hormone

growth hormone

IGF-1

insulin-like growth factor 1

IGFBP-3

insulin-like growth factor-binding protein 3

MRI

magnetic resonance imaging

PSIS

pituitary stalk interruption syndrome

BAV

bicuspid aortic valve

RBCs

red blood cells

NAG

N-acetyl-beta-d-glucosaminidase

RBP

retinol binding protein

NGAL

neutrophil gelatinase-associated lipocalin

GBM

glomerular basement membrane

SRO

shortest region of overlap

TBMN

thin basement membrane nephropathy

luteinizing hormonel

FSH

folicular stimulating hormone

SRNS

steroid resistant nephrotic syndrome

Ethics approval and consent to participate

The studies involving human participants were reviewed and approved by the Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. (Ethics Approval Number: TJ-IRB20201016). Informed written consent was obtained from the patient’s parents.

Consent for publication

Written informed consent was obtained from the patient’s parent or guardian for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

Availability of data and materials

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

This study was supported by the National Key R&D Program of China（2023YFC2706300）

Authors' contributions

A.Y.Y performed the study, participated in data collection, and drafted the manuscript. H.F participated in its design. C.Z and Y.L helped in manuscript drafting. All authors have read and approved the final version of the manuscript.

Acknowledgements

We want to thank the patients and their families for participating in this study.The author would like to express their gratitude to MyGenostics Co. Ltd. in Beijing for their support with sequencing technology.

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Table 5 is available in the Supplementary Files section

No competing interests reported.

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Clinical characteristics and long-term follow-up of twin boys with de novo interstitial 1q25.2q25.3 deletion and 4q35.2 microduplication

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Abstract

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Introduction

Methods

Patients

Copy number variation (CNV) analysis

Exome sequencing of genes associated with glomerular disease

Results

Medical history and Physical examinations

Laboratory Investigations

Genetic Analysis

Treatment and follow-up

Discussion

Abbreviations

Declarations

References

Table

Additional Declarations

Supplementary Files

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