The clinical and genetic characteristics of permanent neonatal diabetes (PNDM) in the state of Qatar

Abstract

Background: Neonatal diabetes mellitus (NDM) is a rare condition that occurs within the first six months of life. Permanent NDM (PNDM) is caused by mutations in specific genes that are known for their expression at early and/or late stages of pancreatic beta- cell development, and are either involved in beta-cell survival, insulin processing, regulation, and release. The native population in Qatar continues to practice consanguineous marriages that lead to a high level of homozygosity. To our knowledge, there is no previous report on the genomics of NDM among the Qatari population. The aims of the current study are to identify patients with NDM diagnosed between 2001 and 2016, and examine their clinical and genetic characteristics.

Methods: To calculate the incidence of PNDM, all patients with PNDM diagnosed between 2001 and 2016 were compared to the total number of live births over the 16-year-period. Whole Genome Sequencing (WGS) was used to investigate the genetic etiology in the PNDM cohort.

Results: PNDM was diagnosed in nine (n = 9) patients with an estimated incidence rate of 1:22,938 live births among the indigenous Qatari. Seven different mutations in six genes (PTF1A, GCK, SLC2A2, EIF2AK3, INS, and HNF1B) were identified. In the majority of cases, the genetic etiology was part of a previously identified autosomal recessive disorder. Two novel de novo mutations were identified in INS and HNF1B.

Conclusion: Qatar has the second highest reported incidence of PNDM worldwide. A majority of PNDM cases present as rare familial autosomal recessive disorders. Pancreas associated transcription factor 1a (PTF1A) enhancer deletions are the most common cause of PNDM in Qatar, with only a few previous cases reported in the literature.

Keywords: GCK; HNF1B; INS; PTF1A; Fanconi-Bickel Syndrome (FBS); Permanent neonatal diabetes (PNDM); Whole Genome Sequencing (WGS); Wolcott-Rallison Syndrome (WRS); pancreatic agenesis.

Figure 1

Patients with PTF1A distal enhancer deletion. (a) WGS analysis showing structural variant (7.62 kb deletion) in chromosome 10:23502416–23510031, located downstream of PTF1A. Pedigree chart of two unrelated consanguineous families, family 1 (b) and family 2 (c). Squares indicate male persons, and circles female persons. The arrow indicates the proband. The open symbols, dotted symbols, and solid symbols represent nonvariant, heterozygote, and homozygous for mutations, respectively. (d) WHO for the height of patient 1. Ultrasound (US) of the abdomen showing pancreatic atrophy (e, f) in patient 1 and 3, respectively. The white arrow points to the atrophied pancreas

Figure 2

Patients with GCK and SLC2A2 Recessive Mutations. (a) Chromatogram obtained using Sanger sequencing confirming GCK homozygosity (c.437T > C) in patient 4 and heterozygosity in both parents and siblings. (b) Pedigree chart significant for first‐degree consanguineous parents in family 4. (c) Chromatogram obtained using Sanger sequencing confirming SLC2A2 homozygosity (c.901C > T) in patient 5 and heterozygosity in both parents. (d) Pedigree chart significant for first‐degree consanguineous parents in family 5. Squares indicate male persons, and circles female persons. The arrow indicates the proband. The open symbols, dotted symbols, and solid symbols represent nonvariant, heterozygote, and homozygous for mutations, respectively

Figure 3

A Patient with Wolcott–Rallison Syndrome (WRS). (a) Chromatogram obtained using Sanger sequencing confirming homozygosity (c.1566_1569delGAAA in exon 9 of EIF2AK3) is patient 6 and heterozygosity in both parents and sibling 1. (b) Pedigree chart significant for first‐degree consanguineous parents in family 6. Squares indicate male persons, and circles female persons. The arrow indicates the proband. The open symbols, dotted symbols, and solid symbols represent nonvariant, heterozygote, and homozygous for mutations, respectively. (c) CT scans and MRA. CT of the head without contrast shows left cerebral atrophy with dilation of the left lateral ventricle. The MRA of the intracranial arteries showed a relative reduction in the caliber of the left MCA with a paucity of the distal branches of the let ACA and MCA compared to the right side. (d) US abdomen before liver transplant: Mild hepatomegaly. The liver is enlarged measuring 10.5 cm with coarse echotexture. US abdomen following liver transplant: The transplanted liver is normal in texture with no focal lesion. Normal flow signals are elicited. The hepatic veins and IVC are patent. Pancreatic head and body show normal thickness and echogenicity

Figure 4

Patients with recessive and dominant novel INS mutations. (a) Chromatogram obtained using Sanger sequencing confirming INS homozygosity c.‐331C > G in patient 7 and her sibling. Heterozygosity shown in both parents. (b) Pedigree chart significant for first‐degree consanguineous parents in family 7. Squares indicate male persons, and circles female persons. The arrow indicates the proband. The open symbols, dotted symbols, and solid symbols represent nonvariant, heterozygote, and homozygous for mutations, respectively. (c) Chromatogram obtained using Sanger sequencing confirming INS de novo c.325T > A. Normal sequencing seen in both parents. (d) Pedigree chart Insignificant for consanguinity in family 7. Squares indicate male persons, and circles female persons. The arrow indicates the proband. The open symbols, and solid symbols represent nonvariant and heterozygote for the mutation, respectively

Figure 5

PNDM due to Novel de novo HNF1B Heterozygous Mutation. (a) Chromatogram obtained using Sanger sequencing confirming HNF1B heterozygosity (c.1099A > G, p.Ser367Gly) in patient 9. (b) Pedigree chart significant for first‐degree consanguineous parents in family 9. Squares indicate male persons, and circles female persons. The arrow indicates the proband. The open symbols, and solid symbols represent nonvariant and heterozygote for the mutation, respectively. (c) Abdominal ultrasound showing hepatosplenomegaly