Maternal UPD of chromosome 7 in a patient with Silver‐Russell syndrome and Pendred syndrome

Abstract Background Silver‐Russell syndrome (SRS) is a heterogeneous imprinting disorder featuring severe intrauterine and postnatal growth retardation and dysmorphic features. Pendred syndrome (PDS) is an autosomal recessive disorder caused by mutations in the SLC26A4 gene characterized by sensorineural hearing loss. Methods Karyotyping analysis was performed to investigate any chromosomal abnormalities. Whole‐genome copy number variation and loss of heterozygosity were analyzed using an Affymetrix CytoScan 750 K Microarray. Variant screening was performed by targeted next‐generation sequencing on all known deafness‐causing genes. Results The proband was a patient with SRS caused by maternal uniparental disomy 7. The PDS of the proband was caused by homozygous variant c.919‐2A > G of SLC26A4; both mutated alleles were inherited from his mother. Conclusion This is the first report of uniparental disomy 7 leading to SRS and Pendred syndrome. Patients with intrauterine growth retardation or those born small for gestational age and exhibiting postnatal growth failure should undergo molecular testing to reach a clinical diagnosis.

abnormalities of the cochlea, sensorineural hearing loss, and diffuse thyroid enlargement (goiter). 6 PDS can be caused by homozygous or compound heterozygous mutations in the SLC26A4 (OMIM 605646) gene on chromosome 7q22. 3. PDS may also rarely be caused by digenic inheritance of a heterozygous mutation in the SLC26A4 gene and a heterozygous mutation in the FOXI1 gene (OMIM, 601093). 7 Mutations in the SLC26A4 gene can also cause autosomal recessive deafness-4 (DFNB4; 600791) with enlarged vestibular aqueduct. 8 In 2018, Cirello 9 reported a case exhibiting both SRS and PDS.
The SRS was caused by segmental maternal UPD7q, and the PDS was caused by homozygous deletion of exons 17-20 of SLC26A4, located at 7q. Here, we study the genetic etiology of a 4-year-old boy with severe developmental delay and hearing loss. By molecular diagnosis, the boy's condition was shown to be caused by maternal

| Sample
The proband was a 4-year-old boy born at 36 weeks by vaginal delivery. He was the first child of healthy nonconsanguineous parents of Chinese Han ethnicity. The birthweight was 1420 g, height was 36 cm, and head circumference was 24 cm. He was transferred to the neonatal intensive care unit because of asphyxia. At 73 days of age, his mental reaction was acceptable, and there were no signs of irritability or convulsions, no apnea, oxygen saturation >80%, and normal blood pressure; the patient was thus discharged from hospital. Hearing loss was first noted during hospitalization by binaural hearing screening. At 4 years of age, the proband visited our hospital for genetic counseling because of severe developmental delay, with height 75 cm and weight 6500 g. Craniofacial dysmorphic features included high forehead, thin lips, low-set posteriorly rotated ears, and mild frontal bossing (Figure 1), along with other features including spina bifida ( Figure 1). This study was performed in accordance with the tenets of the Declaration of Helsinki. This study was also approved by the Ethics Committee of Gansu Provincial Maternal and Child Health Care Hospital. Written informed consent for the publication of this report was obtained from the proband's parents.

| CytoScan 750 K Microarray assay
Whole-genome CNV analysis was performed using Affymetrix CytoScan 750 K Microarray (Thermo Scientific), which contains 550 000 markers for detecting copy number variation and 200 000 high-performing SNP probes, and can perform array-CGH and SNP-array at the same time.
The workflow of the CytoScan ™ assay was performed in accordance with the Affymetrix ® CytoScan ™ Assay protocol. 11

| Microsatellite analysis
Microsatellite analysis was performed using five STR markers (D7S460, D7s821, D7s1818, D7S1804, and D7S2446) spanning the whole of chromosome 7. 12 PCR amplicons were genotyped on capillary electrophoresis using the 3 ABI 3500DX Genetic Analyzer (Applied Biosystems). Data analysis was performed using GeneMapper4 software (Applied Biosystems) matching parental to proband transmission.

| RE SULTS
The karyotypes of the proband and his parents were normal. The  (Table 1).

| D ISCUSS I ON
We identified the etiology of a boy suffering from severe developmental delay and hearing loss. His weight (1420 g) and height (36 cm) were less than −2 SD for his gestational age at birth. Because the proband had received both copies of chromosome 7 from his mother, he presented this variant in homozygous form.
The incidence of SRS was reported to be about 1:30 000 to 1:100 000; 1 however, only about 10% of SRS cases are due to maternal UPD7. 5 PDS is the most common syndromal form of deafness and can be caused by homozygous or compound heterozygous mutation in SLC26A4, which is located on chromosome 7q22.3. Occasionally, recessive disorders may occur as a consequence of duplication or UPD of a region including a heterozygous pathogenic variant. 9 The first international consensus statement on the diagnosis and management of SRS was published in 2016. 1 SRS has variable characteristics, although it is easy to recognize, with typical symptoms such as severe postnatal growth delay and postnatal macrocephaly. 14,15 However, the diagnosis of SRS can be difficult as the condition varies widely in severity among affected individuals and many of its features are nonspecific. 16 and MEST (7q32). 1 In addition to the typical clinical features of SRS, we also found spina bifida in our patient; however, we did not find any gene on chromosome 7 reported to be associated with a predisposition for spina bifida, so we suspected that this might have been a coincidence.
In conclusion, this is the first report of UPD7 leading to SRS and PDS. Via molecular testing, we identified the etiology of the proband. SRS is rare and presents with prenatal and postnatal growth retardation. Molecular tests are recommended for patients with intrauterine growth retardation or those born small for gestational age and exhibiting postnatal growth failure. If a homozygous mutation is identified in a proband but only one parent is a carrier, screening for UPD by SNP-array and microsatellite analysis is advisable.

ACK N OWLED G M ENTS
We would like to thank all the participants in this study. We thank Liwen Bianji, Edanz Group, China (www.liwen bianji.cn/ac), for editing the English text of a draft of this article.